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Zanubrutinib shows worth against standard CLL drugs
MANCHESTER, ENGLAND – A new treatment option may soon be available for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Zanubrutinib (Brukinsa), an irreversible, next-generation Bruton tyrosine kinase (BTK) inhibitor, is designed to minimize the off-target cardiovascular toxicities, such as atrial fibrillation and hypertension, seen with the first-generation ibrutinib (Imbruvica).
Zanubrutinib is already approved for use in mantle cell and marginal zone lymphomas and Waldenström’s macroglobulinemia.
Now it has also shown efficacy in CLL.
However, experts question whether the drug will find its place in an increasingly crowded space for the management of CLL.
Data from two phase 3 trials
The new data from two phase 3 clinical trials were presented recently at the British Society for Haematology 62nd annual scientific meeting, held in Manchester, England.
The ALPINE trial compared zanubrutinib with ibrutinib in 415 patients with CLL/SLL and showed that the novel drug was associated with a significant improvement in overall response rate, at 78% versus 63%.
This first interim analysis also showed that there was an increase in progression-free survival (PFS) with zanubrutinib, and crucially, it was associated with a lower atrial fibrillation/flutter rate than ibrutinib.
“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said lead author Peter Hillmen, MBChB, FRCP, PhD, St. James’s University Hospital, Leeds, England.
The SEQUOIA study looked at zanubrutinib versus bendamustine plus rituximab in patients with untreated CLL/SLL with a 17p deletion and showed that PFS was improved with zanubrutinib by 58%.
Zanubrutinib was also associated with improved overall response rates and was well tolerated.
The results therefore “support the potential utility of zanubrutinib in the frontline management of patients with previously untreated CLL/SLL,” said lead author Talha Munir, MBBS, also of St. James’s University Hospital.
Improvement over ibrutinib
Ibrutinib, the first BTK inhibitor, “truly revolutionized the way we treat CLL,” commented Renata Walewska, MRCP, PhD, consultant hematologist at the Royal Bournemouth (England) Hospital and chair of the UKCLL Forum.
“But it has got quite a lot of, especially cardiac, problems, with atrial fibrillation and hypertension,” she said in an interview. The problem is that it acts not only as an inhibitor of Bruton kinase, but also affects other kinases, she explained.
Zanubrutinib is “much cleaner,” continued Dr. Walewska, who was lead author of the recently published British Society of Haematology guideline for the treatment of CLL.
However, the drug “is not that groundbreaking,” she commented, as acalabrutinib (Calquence), another next-generation BTK inhibitor, is already available for use in the clinic.
“We’re really lucky in CLL,” Dr. Walewska said, “we’ve got so many new drugs available, and it’s getting quite crowded. Trying to find a place for zanubrutinib is going be tricky.”
Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, commented that he “gives a lot of credit” to BeiGene, the company behind zanubrutinib, for “taking on these big studies.”
He said that, with the improvements in PFS and reduced atrial fibrillation with the drug, “there will be many clinicians paying attention to this and zanubrutinib could be preferred over conventional options.”
However, he agreed that it will have to compete with acalabrutinib, adding that, beyond BTK inhibitors, there are “a lot of options” for patients with CLL.
“That makes it very difficult for physicians to figure out what is the best type of therapy” to use in these patients, he added.
Dr. Greenberger told this news organization that further studies will need to demonstrate that zanubrutinib is associated with extended survival, which is “just not possible to show” at the moment with the current follow-up period.
He also noted that, in 10 years, ibrutinib will be off-patent, but zanubrutinib will not, at which point the “substantial” cost of the medication, which is a source of “hardship to patients,” will be increasingly relevant.
Study details
The phase 3 ALPINE study involved 415 adults with CLL/SLL refractory to one or more prior systemic therapies and measurable lymphadenopathy on imaging.
They were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or withdrawal from the study.
Most patients had Binet stage A/B or Ann Arbor stage I/II disease, and 7.3% of patients treated with zanubrutinib and 10.1% of those assigned to ibrutinib had received more than three prior lines of therapy.
Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Over a median follow-up of 14 months, the investigator-assessed 12-month PFS was 94.9% for zanubrutinib and 84.0% for ibrutinib (P = .0007). Overall survival at 12 months was 97% versus 92.7%, but the difference was not significant (P = .1081).
Patients treated with zanubrutinib experienced more grade 3 or higher adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
More importantly, there were fewer cardiac disorders of any grade with zanubrutinib versus ibrutinib, and any-grade atrial fibrillation was significantly less common, at 2.5% versus 10.1% (P = .0014).
Rates of hypertension and hemorrhage were similar between the two treatments, while rates of neutropenia were higher with zanubrutinib versus ibrutinib, at 28.4% versus 21.7%.
The phase 3 SEQUOIA study looked at an earlier stage of disease and included patients with previously untreated CLL/SLL (without 17p depletion) who were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
This trial involved 479 patients randomized to zanubrutinib or bendamustine (days 1 and 2) plus rituximab for six cycles of 28 days each (B+R).
The median age of patients was 70 years, and approximately 80% were at least 65 years old. Just over 60% were men and most (over 70%) were from Europe.
After a median of 26.2 months, independent review committee–assessed PFS was significantly longer with zanubrutinib versus B+R (hazard ratio, 0.42; P < .0001), with an estimated 24-month PFS of 85.5% versus 69.5%.
These results held whether patients were stratified by age, Binet stage, bulky disease, or 11q deletion status, and for patients with an unmutated, but not mutated, immunoglobulin heavy chain gene.
The overall response rate with zanubrutinib was 94.6% versus 85.3% with B+R, and estimated 24-month overall survival was 94.3% versus 94.6%.
Rates of adverse events of any grade were similar between the two treatment groups, although B+R was associated with a higher (grade ≥ 3) adverse event rate, at 79.7%, versus 52.5% for zanubrutinib, and a higher rate of treatment discontinuation because of adverse events, at 13.7% versus 8.3%.
Interestingly, any-grade hypertension was more common with zanubrutinib versus B+R, at 14.2% versus 10.6%, but much lower rates of neutropenia were more common with zanubrutinib, at 15.8% versus 56.8%.
The studies were sponsored by BeiGene. Dr. Hillmen has reported relationships with Janssen, AbbVie, Pharmacyclics, Roche, Gilead, AstraZeneca, SOBI, and BeiGene. Dr. Munir has reported relationships with AbbVie, AstraZeneca, Roche, Alexion, Janssen, MorphoSys, and SOBI. Other authors have also declared numerous relationships.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – A new treatment option may soon be available for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Zanubrutinib (Brukinsa), an irreversible, next-generation Bruton tyrosine kinase (BTK) inhibitor, is designed to minimize the off-target cardiovascular toxicities, such as atrial fibrillation and hypertension, seen with the first-generation ibrutinib (Imbruvica).
Zanubrutinib is already approved for use in mantle cell and marginal zone lymphomas and Waldenström’s macroglobulinemia.
Now it has also shown efficacy in CLL.
However, experts question whether the drug will find its place in an increasingly crowded space for the management of CLL.
Data from two phase 3 trials
The new data from two phase 3 clinical trials were presented recently at the British Society for Haematology 62nd annual scientific meeting, held in Manchester, England.
The ALPINE trial compared zanubrutinib with ibrutinib in 415 patients with CLL/SLL and showed that the novel drug was associated with a significant improvement in overall response rate, at 78% versus 63%.
This first interim analysis also showed that there was an increase in progression-free survival (PFS) with zanubrutinib, and crucially, it was associated with a lower atrial fibrillation/flutter rate than ibrutinib.
“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said lead author Peter Hillmen, MBChB, FRCP, PhD, St. James’s University Hospital, Leeds, England.
The SEQUOIA study looked at zanubrutinib versus bendamustine plus rituximab in patients with untreated CLL/SLL with a 17p deletion and showed that PFS was improved with zanubrutinib by 58%.
Zanubrutinib was also associated with improved overall response rates and was well tolerated.
The results therefore “support the potential utility of zanubrutinib in the frontline management of patients with previously untreated CLL/SLL,” said lead author Talha Munir, MBBS, also of St. James’s University Hospital.
Improvement over ibrutinib
Ibrutinib, the first BTK inhibitor, “truly revolutionized the way we treat CLL,” commented Renata Walewska, MRCP, PhD, consultant hematologist at the Royal Bournemouth (England) Hospital and chair of the UKCLL Forum.
“But it has got quite a lot of, especially cardiac, problems, with atrial fibrillation and hypertension,” she said in an interview. The problem is that it acts not only as an inhibitor of Bruton kinase, but also affects other kinases, she explained.
Zanubrutinib is “much cleaner,” continued Dr. Walewska, who was lead author of the recently published British Society of Haematology guideline for the treatment of CLL.
However, the drug “is not that groundbreaking,” she commented, as acalabrutinib (Calquence), another next-generation BTK inhibitor, is already available for use in the clinic.
“We’re really lucky in CLL,” Dr. Walewska said, “we’ve got so many new drugs available, and it’s getting quite crowded. Trying to find a place for zanubrutinib is going be tricky.”
Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, commented that he “gives a lot of credit” to BeiGene, the company behind zanubrutinib, for “taking on these big studies.”
He said that, with the improvements in PFS and reduced atrial fibrillation with the drug, “there will be many clinicians paying attention to this and zanubrutinib could be preferred over conventional options.”
However, he agreed that it will have to compete with acalabrutinib, adding that, beyond BTK inhibitors, there are “a lot of options” for patients with CLL.
“That makes it very difficult for physicians to figure out what is the best type of therapy” to use in these patients, he added.
Dr. Greenberger told this news organization that further studies will need to demonstrate that zanubrutinib is associated with extended survival, which is “just not possible to show” at the moment with the current follow-up period.
He also noted that, in 10 years, ibrutinib will be off-patent, but zanubrutinib will not, at which point the “substantial” cost of the medication, which is a source of “hardship to patients,” will be increasingly relevant.
Study details
The phase 3 ALPINE study involved 415 adults with CLL/SLL refractory to one or more prior systemic therapies and measurable lymphadenopathy on imaging.
They were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or withdrawal from the study.
Most patients had Binet stage A/B or Ann Arbor stage I/II disease, and 7.3% of patients treated with zanubrutinib and 10.1% of those assigned to ibrutinib had received more than three prior lines of therapy.
Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Over a median follow-up of 14 months, the investigator-assessed 12-month PFS was 94.9% for zanubrutinib and 84.0% for ibrutinib (P = .0007). Overall survival at 12 months was 97% versus 92.7%, but the difference was not significant (P = .1081).
Patients treated with zanubrutinib experienced more grade 3 or higher adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
More importantly, there were fewer cardiac disorders of any grade with zanubrutinib versus ibrutinib, and any-grade atrial fibrillation was significantly less common, at 2.5% versus 10.1% (P = .0014).
Rates of hypertension and hemorrhage were similar between the two treatments, while rates of neutropenia were higher with zanubrutinib versus ibrutinib, at 28.4% versus 21.7%.
The phase 3 SEQUOIA study looked at an earlier stage of disease and included patients with previously untreated CLL/SLL (without 17p depletion) who were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
This trial involved 479 patients randomized to zanubrutinib or bendamustine (days 1 and 2) plus rituximab for six cycles of 28 days each (B+R).
The median age of patients was 70 years, and approximately 80% were at least 65 years old. Just over 60% were men and most (over 70%) were from Europe.
After a median of 26.2 months, independent review committee–assessed PFS was significantly longer with zanubrutinib versus B+R (hazard ratio, 0.42; P < .0001), with an estimated 24-month PFS of 85.5% versus 69.5%.
These results held whether patients were stratified by age, Binet stage, bulky disease, or 11q deletion status, and for patients with an unmutated, but not mutated, immunoglobulin heavy chain gene.
The overall response rate with zanubrutinib was 94.6% versus 85.3% with B+R, and estimated 24-month overall survival was 94.3% versus 94.6%.
Rates of adverse events of any grade were similar between the two treatment groups, although B+R was associated with a higher (grade ≥ 3) adverse event rate, at 79.7%, versus 52.5% for zanubrutinib, and a higher rate of treatment discontinuation because of adverse events, at 13.7% versus 8.3%.
Interestingly, any-grade hypertension was more common with zanubrutinib versus B+R, at 14.2% versus 10.6%, but much lower rates of neutropenia were more common with zanubrutinib, at 15.8% versus 56.8%.
The studies were sponsored by BeiGene. Dr. Hillmen has reported relationships with Janssen, AbbVie, Pharmacyclics, Roche, Gilead, AstraZeneca, SOBI, and BeiGene. Dr. Munir has reported relationships with AbbVie, AstraZeneca, Roche, Alexion, Janssen, MorphoSys, and SOBI. Other authors have also declared numerous relationships.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – A new treatment option may soon be available for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Zanubrutinib (Brukinsa), an irreversible, next-generation Bruton tyrosine kinase (BTK) inhibitor, is designed to minimize the off-target cardiovascular toxicities, such as atrial fibrillation and hypertension, seen with the first-generation ibrutinib (Imbruvica).
Zanubrutinib is already approved for use in mantle cell and marginal zone lymphomas and Waldenström’s macroglobulinemia.
Now it has also shown efficacy in CLL.
However, experts question whether the drug will find its place in an increasingly crowded space for the management of CLL.
Data from two phase 3 trials
The new data from two phase 3 clinical trials were presented recently at the British Society for Haematology 62nd annual scientific meeting, held in Manchester, England.
The ALPINE trial compared zanubrutinib with ibrutinib in 415 patients with CLL/SLL and showed that the novel drug was associated with a significant improvement in overall response rate, at 78% versus 63%.
This first interim analysis also showed that there was an increase in progression-free survival (PFS) with zanubrutinib, and crucially, it was associated with a lower atrial fibrillation/flutter rate than ibrutinib.
“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said lead author Peter Hillmen, MBChB, FRCP, PhD, St. James’s University Hospital, Leeds, England.
The SEQUOIA study looked at zanubrutinib versus bendamustine plus rituximab in patients with untreated CLL/SLL with a 17p deletion and showed that PFS was improved with zanubrutinib by 58%.
Zanubrutinib was also associated with improved overall response rates and was well tolerated.
The results therefore “support the potential utility of zanubrutinib in the frontline management of patients with previously untreated CLL/SLL,” said lead author Talha Munir, MBBS, also of St. James’s University Hospital.
Improvement over ibrutinib
Ibrutinib, the first BTK inhibitor, “truly revolutionized the way we treat CLL,” commented Renata Walewska, MRCP, PhD, consultant hematologist at the Royal Bournemouth (England) Hospital and chair of the UKCLL Forum.
“But it has got quite a lot of, especially cardiac, problems, with atrial fibrillation and hypertension,” she said in an interview. The problem is that it acts not only as an inhibitor of Bruton kinase, but also affects other kinases, she explained.
Zanubrutinib is “much cleaner,” continued Dr. Walewska, who was lead author of the recently published British Society of Haematology guideline for the treatment of CLL.
However, the drug “is not that groundbreaking,” she commented, as acalabrutinib (Calquence), another next-generation BTK inhibitor, is already available for use in the clinic.
“We’re really lucky in CLL,” Dr. Walewska said, “we’ve got so many new drugs available, and it’s getting quite crowded. Trying to find a place for zanubrutinib is going be tricky.”
Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, commented that he “gives a lot of credit” to BeiGene, the company behind zanubrutinib, for “taking on these big studies.”
He said that, with the improvements in PFS and reduced atrial fibrillation with the drug, “there will be many clinicians paying attention to this and zanubrutinib could be preferred over conventional options.”
However, he agreed that it will have to compete with acalabrutinib, adding that, beyond BTK inhibitors, there are “a lot of options” for patients with CLL.
“That makes it very difficult for physicians to figure out what is the best type of therapy” to use in these patients, he added.
Dr. Greenberger told this news organization that further studies will need to demonstrate that zanubrutinib is associated with extended survival, which is “just not possible to show” at the moment with the current follow-up period.
He also noted that, in 10 years, ibrutinib will be off-patent, but zanubrutinib will not, at which point the “substantial” cost of the medication, which is a source of “hardship to patients,” will be increasingly relevant.
Study details
The phase 3 ALPINE study involved 415 adults with CLL/SLL refractory to one or more prior systemic therapies and measurable lymphadenopathy on imaging.
They were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or withdrawal from the study.
Most patients had Binet stage A/B or Ann Arbor stage I/II disease, and 7.3% of patients treated with zanubrutinib and 10.1% of those assigned to ibrutinib had received more than three prior lines of therapy.
Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Over a median follow-up of 14 months, the investigator-assessed 12-month PFS was 94.9% for zanubrutinib and 84.0% for ibrutinib (P = .0007). Overall survival at 12 months was 97% versus 92.7%, but the difference was not significant (P = .1081).
Patients treated with zanubrutinib experienced more grade 3 or higher adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
More importantly, there were fewer cardiac disorders of any grade with zanubrutinib versus ibrutinib, and any-grade atrial fibrillation was significantly less common, at 2.5% versus 10.1% (P = .0014).
Rates of hypertension and hemorrhage were similar between the two treatments, while rates of neutropenia were higher with zanubrutinib versus ibrutinib, at 28.4% versus 21.7%.
The phase 3 SEQUOIA study looked at an earlier stage of disease and included patients with previously untreated CLL/SLL (without 17p depletion) who were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
This trial involved 479 patients randomized to zanubrutinib or bendamustine (days 1 and 2) plus rituximab for six cycles of 28 days each (B+R).
The median age of patients was 70 years, and approximately 80% were at least 65 years old. Just over 60% were men and most (over 70%) were from Europe.
After a median of 26.2 months, independent review committee–assessed PFS was significantly longer with zanubrutinib versus B+R (hazard ratio, 0.42; P < .0001), with an estimated 24-month PFS of 85.5% versus 69.5%.
These results held whether patients were stratified by age, Binet stage, bulky disease, or 11q deletion status, and for patients with an unmutated, but not mutated, immunoglobulin heavy chain gene.
The overall response rate with zanubrutinib was 94.6% versus 85.3% with B+R, and estimated 24-month overall survival was 94.3% versus 94.6%.
Rates of adverse events of any grade were similar between the two treatment groups, although B+R was associated with a higher (grade ≥ 3) adverse event rate, at 79.7%, versus 52.5% for zanubrutinib, and a higher rate of treatment discontinuation because of adverse events, at 13.7% versus 8.3%.
Interestingly, any-grade hypertension was more common with zanubrutinib versus B+R, at 14.2% versus 10.6%, but much lower rates of neutropenia were more common with zanubrutinib, at 15.8% versus 56.8%.
The studies were sponsored by BeiGene. Dr. Hillmen has reported relationships with Janssen, AbbVie, Pharmacyclics, Roche, Gilead, AstraZeneca, SOBI, and BeiGene. Dr. Munir has reported relationships with AbbVie, AstraZeneca, Roche, Alexion, Janssen, MorphoSys, and SOBI. Other authors have also declared numerous relationships.
A version of this article first appeared on Medscape.com.
When CPI fails, HL patients should get timely allo-HCT
In fact, prior treatment with PD-1–directed therapies nivolumab (Opdivo) and pembrolizumab (Keytruda) appears to improve outcomes in allo-HCT patients, said Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center in New York.
“The use of allogeneic HCT is decreasing for Hodgkin even though it is a curative option, and we see patients referred after they have had multiple lines of therapy,” Dr. Perales said in an interview. “The lymphoma MDs have a perception that outcomes are poor, and therefore don’t refer.”
To illustrate his point, Dr. Perales shared data from the EBMT database. In 2014, the registry accrued approximately 450 allo-HCT cases; by 2021 this had fallen to fewer than 200 procedures.
Ironically, this declining enthusiasm for transplantation coincides with a steady improvement in transplant outcomes following PD-1 blockade, Dr. Perales noted. For example, an analysis, published in Nature, yielded an 82% overall survival (OS) at 3 years in patients who underwent allo-HCT after CPI treatment (n =209).
“Results of allo-HCT in patients with Hodgkin show a remarkable cure rate,” said Dr. Perales. “Part of that is probably driven by lower relapse due to enhanced graft-versus-lymphoma effect due to long CPI half-life.” (The half-lives of pembrolizumab and nivolumab are 22 and 25 days, respectively.)
At the EBMT meeting, Dr. Perales presented a new retrospective analysis that tested the hypothesis that CPIs might actually improve outcomes for allo-HCT patients. An international team of clinicians from EBMT and the Center for International Blood and Marrow Transplant Research (CIBMTR) compared allo-HCT outcomes with (n = 347) and without (n = 1,382) prior treatment with a checkpoint inhibitor.
They found that prior CPI therapy was, indeed, associated with lower relapse (hazard ratio, 0.53; P = .00023) and longer progression-free survival (PFS) (HR, 0.75; P = .0171).
However, prior PD-1 drugs provided no survival advantage, Dr. Perales said. “The easiest explanation for a study showing a difference in PFS/relapse, not OS, is that we have good treatments that can treat patients who relapse and so their overall survival ends up being the same.”
The researchers also confirmed previous reports that patients who received PD-1 inhibitors prior to transplant had a higher incidence of GVHD. Prevalence of acute grades 2-4 GVHD was significantly higher (P = .027); however, acute grades 3-4 GVHD and chronic GVHD were not significantly different between the two groups.
Dr. Perales speculated that the use of posttransplant cyclophosphamide for GVHD prophylaxis would mitigate the risk of GVHD associated with PD-1 inhibitors, “we have not yet proven that formally ... [we] are still analyzing our data.”
Commenting on the results of the new analysis, Dr. Perales expressed concern that patients are being recruited to early-phase clinical trials after failing on a checkpoint inhibitor, instead of being offered allo-HCT – a potentially curative treatment – because treaters are misinformed about the safety of transplant after these drugs.
The NIH clinical-trials database backs up Dr. Perales’ worries. In the United States, for example, there are currently 19 trials recruiting for relapsed/refractory Hodgkin lymphoma patients prior to transplant. Of these, 15 studies permit enrollment of patients who have failed on CPIs, and 8 are phase 1 or 2 studies.
“The good news is that new drugs, including CPIs, have dramatically changed outcomes in this disease and that fewer patients now need an allo-HCT,” said Dr. Perales. And if a transplant is needed, “it is safe to perform allo-HCT in patients treated with prior CPI.”
However, time is of the essence. “Patients with Hodgkin lymphoma should be referred to allo-HCT if they are not responding or tolerating CPI, rather than go on a series of phase 1 trials,” Dr. Perales said. “Median age is 32, and we should be going for a cure, nothing less.”
Dr. Perales reported receiving honoraria from numerous pharmaceutical companies; serving on the data and safety monitoring boards of Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serving on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.
In fact, prior treatment with PD-1–directed therapies nivolumab (Opdivo) and pembrolizumab (Keytruda) appears to improve outcomes in allo-HCT patients, said Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center in New York.
“The use of allogeneic HCT is decreasing for Hodgkin even though it is a curative option, and we see patients referred after they have had multiple lines of therapy,” Dr. Perales said in an interview. “The lymphoma MDs have a perception that outcomes are poor, and therefore don’t refer.”
To illustrate his point, Dr. Perales shared data from the EBMT database. In 2014, the registry accrued approximately 450 allo-HCT cases; by 2021 this had fallen to fewer than 200 procedures.
Ironically, this declining enthusiasm for transplantation coincides with a steady improvement in transplant outcomes following PD-1 blockade, Dr. Perales noted. For example, an analysis, published in Nature, yielded an 82% overall survival (OS) at 3 years in patients who underwent allo-HCT after CPI treatment (n =209).
“Results of allo-HCT in patients with Hodgkin show a remarkable cure rate,” said Dr. Perales. “Part of that is probably driven by lower relapse due to enhanced graft-versus-lymphoma effect due to long CPI half-life.” (The half-lives of pembrolizumab and nivolumab are 22 and 25 days, respectively.)
At the EBMT meeting, Dr. Perales presented a new retrospective analysis that tested the hypothesis that CPIs might actually improve outcomes for allo-HCT patients. An international team of clinicians from EBMT and the Center for International Blood and Marrow Transplant Research (CIBMTR) compared allo-HCT outcomes with (n = 347) and without (n = 1,382) prior treatment with a checkpoint inhibitor.
They found that prior CPI therapy was, indeed, associated with lower relapse (hazard ratio, 0.53; P = .00023) and longer progression-free survival (PFS) (HR, 0.75; P = .0171).
However, prior PD-1 drugs provided no survival advantage, Dr. Perales said. “The easiest explanation for a study showing a difference in PFS/relapse, not OS, is that we have good treatments that can treat patients who relapse and so their overall survival ends up being the same.”
The researchers also confirmed previous reports that patients who received PD-1 inhibitors prior to transplant had a higher incidence of GVHD. Prevalence of acute grades 2-4 GVHD was significantly higher (P = .027); however, acute grades 3-4 GVHD and chronic GVHD were not significantly different between the two groups.
Dr. Perales speculated that the use of posttransplant cyclophosphamide for GVHD prophylaxis would mitigate the risk of GVHD associated with PD-1 inhibitors, “we have not yet proven that formally ... [we] are still analyzing our data.”
Commenting on the results of the new analysis, Dr. Perales expressed concern that patients are being recruited to early-phase clinical trials after failing on a checkpoint inhibitor, instead of being offered allo-HCT – a potentially curative treatment – because treaters are misinformed about the safety of transplant after these drugs.
The NIH clinical-trials database backs up Dr. Perales’ worries. In the United States, for example, there are currently 19 trials recruiting for relapsed/refractory Hodgkin lymphoma patients prior to transplant. Of these, 15 studies permit enrollment of patients who have failed on CPIs, and 8 are phase 1 or 2 studies.
“The good news is that new drugs, including CPIs, have dramatically changed outcomes in this disease and that fewer patients now need an allo-HCT,” said Dr. Perales. And if a transplant is needed, “it is safe to perform allo-HCT in patients treated with prior CPI.”
However, time is of the essence. “Patients with Hodgkin lymphoma should be referred to allo-HCT if they are not responding or tolerating CPI, rather than go on a series of phase 1 trials,” Dr. Perales said. “Median age is 32, and we should be going for a cure, nothing less.”
Dr. Perales reported receiving honoraria from numerous pharmaceutical companies; serving on the data and safety monitoring boards of Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serving on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.
In fact, prior treatment with PD-1–directed therapies nivolumab (Opdivo) and pembrolizumab (Keytruda) appears to improve outcomes in allo-HCT patients, said Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center in New York.
“The use of allogeneic HCT is decreasing for Hodgkin even though it is a curative option, and we see patients referred after they have had multiple lines of therapy,” Dr. Perales said in an interview. “The lymphoma MDs have a perception that outcomes are poor, and therefore don’t refer.”
To illustrate his point, Dr. Perales shared data from the EBMT database. In 2014, the registry accrued approximately 450 allo-HCT cases; by 2021 this had fallen to fewer than 200 procedures.
Ironically, this declining enthusiasm for transplantation coincides with a steady improvement in transplant outcomes following PD-1 blockade, Dr. Perales noted. For example, an analysis, published in Nature, yielded an 82% overall survival (OS) at 3 years in patients who underwent allo-HCT after CPI treatment (n =209).
“Results of allo-HCT in patients with Hodgkin show a remarkable cure rate,” said Dr. Perales. “Part of that is probably driven by lower relapse due to enhanced graft-versus-lymphoma effect due to long CPI half-life.” (The half-lives of pembrolizumab and nivolumab are 22 and 25 days, respectively.)
At the EBMT meeting, Dr. Perales presented a new retrospective analysis that tested the hypothesis that CPIs might actually improve outcomes for allo-HCT patients. An international team of clinicians from EBMT and the Center for International Blood and Marrow Transplant Research (CIBMTR) compared allo-HCT outcomes with (n = 347) and without (n = 1,382) prior treatment with a checkpoint inhibitor.
They found that prior CPI therapy was, indeed, associated with lower relapse (hazard ratio, 0.53; P = .00023) and longer progression-free survival (PFS) (HR, 0.75; P = .0171).
However, prior PD-1 drugs provided no survival advantage, Dr. Perales said. “The easiest explanation for a study showing a difference in PFS/relapse, not OS, is that we have good treatments that can treat patients who relapse and so their overall survival ends up being the same.”
The researchers also confirmed previous reports that patients who received PD-1 inhibitors prior to transplant had a higher incidence of GVHD. Prevalence of acute grades 2-4 GVHD was significantly higher (P = .027); however, acute grades 3-4 GVHD and chronic GVHD were not significantly different between the two groups.
Dr. Perales speculated that the use of posttransplant cyclophosphamide for GVHD prophylaxis would mitigate the risk of GVHD associated with PD-1 inhibitors, “we have not yet proven that formally ... [we] are still analyzing our data.”
Commenting on the results of the new analysis, Dr. Perales expressed concern that patients are being recruited to early-phase clinical trials after failing on a checkpoint inhibitor, instead of being offered allo-HCT – a potentially curative treatment – because treaters are misinformed about the safety of transplant after these drugs.
The NIH clinical-trials database backs up Dr. Perales’ worries. In the United States, for example, there are currently 19 trials recruiting for relapsed/refractory Hodgkin lymphoma patients prior to transplant. Of these, 15 studies permit enrollment of patients who have failed on CPIs, and 8 are phase 1 or 2 studies.
“The good news is that new drugs, including CPIs, have dramatically changed outcomes in this disease and that fewer patients now need an allo-HCT,” said Dr. Perales. And if a transplant is needed, “it is safe to perform allo-HCT in patients treated with prior CPI.”
However, time is of the essence. “Patients with Hodgkin lymphoma should be referred to allo-HCT if they are not responding or tolerating CPI, rather than go on a series of phase 1 trials,” Dr. Perales said. “Median age is 32, and we should be going for a cure, nothing less.”
Dr. Perales reported receiving honoraria from numerous pharmaceutical companies; serving on the data and safety monitoring boards of Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serving on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.
Survivor’s story foreshadows one of oncology’s greatest successes
At 32 years old, the world was at Larry Unger’s feet. He was vice president at one of Wall Street’s most successful investment management firms, selling mutual funds to more than 1,000 brokers across New York. His clients relied on him for good advice, great jokes, and superlative Yankees tickets. His recent memories included fraternity days at Cornell University and a Harvard law degree. His childhood on the Lower East Side was behind him. He had his own apartment and a beautiful girlfriend.
Then his back started hurting, and he was drenched in sweat at night. His physician suggested it was a basketball injury. Weeks of tests followed, and he changed doctors. Mr. Unger met with an oncologist at Memorial Sloan Kettering Cancer Center who wouldn’t let him go home after the appointment. The next day brought exploratory surgery and an answer to all the questions.
Mr. Unger was diagnosed with stage IIIB Hodgkin lymphoma.
Thirty years later, Mr. Unger credited his survival to the late Subhash Gulati, MD, PhD, then MSKCC’s director of stem cell transplantation. He still recalls Dr. Gulati’s words to him: “Radical situations call for radical solutions.” In 1992, that “radical solution” was an autologous bone-marrow transplant.
“Mr. Unger was a patient pioneer,” said Kenneth Offit, MD, another MSKCC oncologist who also cared for him at that time.
Transplantation for Hodgkin: The early 90s
Hodgkin lymphoma is fairly rare, accounting for just 0.5% of all cancers and 15% of lymphomas. It tends to target young, male adults like Mr. Unger. Today 88% of patients with Hodgkin survive at least 5 years.
When Dr. Gulati offered Mr. Unger his “radical solution” 3 decades ago, the idea of autologous bone marrow transplantation in Hodgkin lymphoma was not new. The first attempt appeared in the literature in the 1950s, but it was still unclear how patients could survive the procedure. It involved destroying the patient’s own immune system prior to the transplant, a huge risk in itself. Worse, the patient was pummeled with chemotherapy and/or radiation to clear out the cancerous bone marrow – a process called “conditioning.”
However, throughout the 1980s, MSKCC had been running clinical trials to perfect the conditioning mix, so by 1992 Dr. Gulati was well-placed to help Mr. Unger.
It is unclear what conditioning Mr. Unger received because his records were not made available. However, around the time that Mr. Unger underwent his transplant, Dr. Gulati and colleagues published the conditioning regimens in use at MSKCC. Patients with refractory or relapsed Hodgkin disease received a conditioning mix of total nodal irradiation (TNI), etoposide (Vepesid) and cyclophosphamide. Patients who had already been through radiotherapy were given carmustine instead of TNI.
In that early publication, Dr. Gulati and the MSKCC team reported 0 “toxic deaths” with the TNI mix, and at the 2-year point 75% of the patients were still alive (n = 28). Patients who had already received radiation treatment did less well, with 55% survival at 2 years, at a cost of 14% toxic deaths (n = 22).
Mr. Unger’s experience, 30 years ago
According to Mr. Unger, the initial treatment for his stage IIIB Hodgkin lymphoma was MOPP (mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, and prednisone) plus ABVD (doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine).
“They wanted to give me two chemo programs at once because they said I was very sick,” Mr. Unger recalled. “I wound up staying in the hospital quite a bit because every time I got these [treatments] I’d get a fever. This went on for month after month after month. Finally, they said: ‘The tumors are starting to shrink. ... I want you to meet Dr. Gulati.’ ”
Mr. Unger said that Dr. Gulati told him: “There is another procedure called the bone marrow transplant which we’ve been doing. This would be like hitting it with a nuclear weapon. We would really wipe it out and make sure that you never come back.”
The alternative was high-dose radiotherapy. However, Dr. Gulati shared MSKCC’s hard-won knowledge that an autologous transplant was less successful after radiation. Dr. Gulati also told Mr. Unger that surgery was needed before the transplant: a laparotomy to restage his tumors.
After discussing the situation with his father, Mr. Unger decided to undergo the transplant.
The night before treatment started, he was laughing and joking with a friend in his room at MSKCC. The next day, the laughing stopped. The conditioning, he said, “was harrowing beyond belief ... 100 times worse than the chemo.”
Chemotherapy came first, followed 2 days later by radiation, presumably TNI. Mr. Unger experienced constant vomiting, intraocular bleeding and high fevers; the soft tissue of his throat “fell apart,” he said.
“I couldn’t move. It was like being dead,” he said. “Finally, maybe after a month or so, I could finally have a little water.” Mr. Unger said his immune system took 6-8 weeks to recover. He concluded, with heroic understatement, “it was rough.”
The battle against Hodgkin was over, but fallout from the chemotherapy lingered. Although Mr. Unger was able to return to his family and the job he loved, in the following years he was never entirely well. He contracted shingles soon after his transplant, then diabetes within 15 years. A heart attack followed in 2008 then, in 2015, an autoimmune disease that still affects his mobility.
However, Mr. Unger remains grateful: “The fact that we did these cutting-edge techniques with me got me to the point where – although I had some problems afterward, and I have problems now – it gave me well over 30 years of a really great life.”
“There are a lot of good doctors out there,” he added. “Some of them go to extraordinary lengths to help people. I try to do the same with the extra 30 years I’ve been given, try to be nice to people and make people feel good. I don’t really see any other reason to be on earth.”
Treatment for Hodgkin lymphoma: 2022
For a comparison of Mr. Unger’s experience with the current approach to Hodgkin lymphoma, this news organization spoke to Miguel-Angel Perales, MD, current chief of the adult bone marrow transplant service at MSKCC. Although Dr. Perales could not comment specifically on Mr. Unger’s case without his records, Dr. Perales was able to review the revolutions in treatment for all patients over the past 30 years.
Certainly, physicians no longer need to inflict a laparotomy on patients just to stage the disease, Dr. Perales said. “This sounds barbaric today. Nowadays we have PET scans.”
Another key change, Dr. Perales said, is in the up-front management of the disease.
For example, MOPP “is going back to the prehistory of chemotherapy,” Dr. Perales said. He was not surprised to learn that Mr. Unger later developed complications such as diabetes and heart disease.
“We’ve completely revolutionized the treatment,” Dr. Perales said. “We [now] use combinations that are much less toxic than MOPP, [and] we’re curing more patients up front.” Treatment is tailored by stage and the likelihood of response to therapy. Aggressive approaches are reserved for patients more likely to fail treatment.
Pretransplant conditioning has also changed for the better, with less toxicity and fewer long-term complications. Total body irradiation has “fallen by the wayside,” said Dr. Perales. Instead, patients get BEAM, a combination of carmustine, etoposide, cytarabine (Cytosar-U, Ara-C), and melphalan (Alkeran), 1 week before the transplant.
Perhaps the most profound change, which began in the 1990s shortly after Larry’s transplant, was that peripheral-blood stem cells gradually replaced bone marrow for both autologous and allogeneic transplant. In 2022, nearly all autologous transplants use peripheral-blood stem cells.
Instead of onerous bone-marrow aspiration in the operating room, the stem cells are collected from the patient’s blood. First, the patient’s bone marrow is hyperstimulated with high doses of filgrastim (G-CSF, Neupogen, Granix) for several days. Stem cells spill into the patient’s blood. Once blood is collected from the patient, the stem cells are separated and stored ready for the transplant. (In theory, stem cell products are “cancer free”; in practice there may be some contaminating cells, said Dr. Perales.)
Nowadays “transplanting” the stem cells back into the body bears no relation to what happened in 1992. The stem-cell infusion is typically an outpatient procedure, and one-third of patients may never be admitted to the hospital at all.
In contrast to Mr. Unger’s excruciating 8-week hospital stay, immune recovery currently takes 12-14 days, often entirely in the patient’s own home, with the option of extra filgrastim to speed things up.
Despite these profound changes, said Dr. Perales, the real quantum leap has occurred post transplant.
In 2015, a multinational team led by MSKCC’s Dr. Craig Moskowitz published a trial in the Lancet showing that brentuximab vedotin halved the risk of relapse after autologous transplantation in high-risk Hodgkin lymphoma patients versus placebo (hazard ratio, 0.57; P = .0013; n = 329). The CD30-directed antibody-drug conjugate was so successful that the placebo patients were encouraged to cross over into the treatment group; many of them were salvaged.
As a result, Dr. Perales said, brentuximab vedotin has now become the standard in high-risk Hodgkin patients following a transplant.
The checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) have also been “transformational” in Hodgkin lymphoma, Dr. Perales said. He explained that Hodgkin lymphoma is “exquisitely sensitive” to these therapies because the disease expresses high levels of the binding proteins for these drugs. This allows the immunotherapies to hit both the immune system and the disease.
Most cancers have response rates for checkpoint inhibitors below 40%, according to a recent analysis by Anas Younes, former chief of lymphoma at MSKCC, and his colleague Eri Matsuki, then a visiting fellow. By contrast, in Hodgkin lymphoma response to these drugs is 66%-87%.
Dr. Perales said: “It tells you how effective these drugs are, that we could move from somebody getting MOPP, which is like throwing a nuclear bomb at somebody, to a combination of two drugs that can easily be given out-patient and that have very little, if any, side effects.”
The future: No chemo, no transplants?
“One of the holy grails in Hodgkin would be if we could treat patients with the combination of a checkpoint inhibitor and brentuximab and what is being termed the ‘chemotherapy-free’ approach to Hodgkin disease,” said Dr. Perales.
What else remains to be done in the world of transplants for Hodgkin lymphoma?
Dr. Perales didn’t hesitate: “To eliminate the need for them. If we can have better targeted therapy up front that cures more patients, then we never even have to consider transplant. Basically, to put me out of work. I’m sure I’ll find other things to do.”
The current treatment of Hodgkin lymphoma “is really what we all consider one of the successes in oncology,” said Dr. Perales. “It’s a beautiful story.”
Dr. Perales reported receiving honoraria from numerous pharmaceutical companies; serves on data and safety monitoring boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serves on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.
At 32 years old, the world was at Larry Unger’s feet. He was vice president at one of Wall Street’s most successful investment management firms, selling mutual funds to more than 1,000 brokers across New York. His clients relied on him for good advice, great jokes, and superlative Yankees tickets. His recent memories included fraternity days at Cornell University and a Harvard law degree. His childhood on the Lower East Side was behind him. He had his own apartment and a beautiful girlfriend.
Then his back started hurting, and he was drenched in sweat at night. His physician suggested it was a basketball injury. Weeks of tests followed, and he changed doctors. Mr. Unger met with an oncologist at Memorial Sloan Kettering Cancer Center who wouldn’t let him go home after the appointment. The next day brought exploratory surgery and an answer to all the questions.
Mr. Unger was diagnosed with stage IIIB Hodgkin lymphoma.
Thirty years later, Mr. Unger credited his survival to the late Subhash Gulati, MD, PhD, then MSKCC’s director of stem cell transplantation. He still recalls Dr. Gulati’s words to him: “Radical situations call for radical solutions.” In 1992, that “radical solution” was an autologous bone-marrow transplant.
“Mr. Unger was a patient pioneer,” said Kenneth Offit, MD, another MSKCC oncologist who also cared for him at that time.
Transplantation for Hodgkin: The early 90s
Hodgkin lymphoma is fairly rare, accounting for just 0.5% of all cancers and 15% of lymphomas. It tends to target young, male adults like Mr. Unger. Today 88% of patients with Hodgkin survive at least 5 years.
When Dr. Gulati offered Mr. Unger his “radical solution” 3 decades ago, the idea of autologous bone marrow transplantation in Hodgkin lymphoma was not new. The first attempt appeared in the literature in the 1950s, but it was still unclear how patients could survive the procedure. It involved destroying the patient’s own immune system prior to the transplant, a huge risk in itself. Worse, the patient was pummeled with chemotherapy and/or radiation to clear out the cancerous bone marrow – a process called “conditioning.”
However, throughout the 1980s, MSKCC had been running clinical trials to perfect the conditioning mix, so by 1992 Dr. Gulati was well-placed to help Mr. Unger.
It is unclear what conditioning Mr. Unger received because his records were not made available. However, around the time that Mr. Unger underwent his transplant, Dr. Gulati and colleagues published the conditioning regimens in use at MSKCC. Patients with refractory or relapsed Hodgkin disease received a conditioning mix of total nodal irradiation (TNI), etoposide (Vepesid) and cyclophosphamide. Patients who had already been through radiotherapy were given carmustine instead of TNI.
In that early publication, Dr. Gulati and the MSKCC team reported 0 “toxic deaths” with the TNI mix, and at the 2-year point 75% of the patients were still alive (n = 28). Patients who had already received radiation treatment did less well, with 55% survival at 2 years, at a cost of 14% toxic deaths (n = 22).
Mr. Unger’s experience, 30 years ago
According to Mr. Unger, the initial treatment for his stage IIIB Hodgkin lymphoma was MOPP (mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, and prednisone) plus ABVD (doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine).
“They wanted to give me two chemo programs at once because they said I was very sick,” Mr. Unger recalled. “I wound up staying in the hospital quite a bit because every time I got these [treatments] I’d get a fever. This went on for month after month after month. Finally, they said: ‘The tumors are starting to shrink. ... I want you to meet Dr. Gulati.’ ”
Mr. Unger said that Dr. Gulati told him: “There is another procedure called the bone marrow transplant which we’ve been doing. This would be like hitting it with a nuclear weapon. We would really wipe it out and make sure that you never come back.”
The alternative was high-dose radiotherapy. However, Dr. Gulati shared MSKCC’s hard-won knowledge that an autologous transplant was less successful after radiation. Dr. Gulati also told Mr. Unger that surgery was needed before the transplant: a laparotomy to restage his tumors.
After discussing the situation with his father, Mr. Unger decided to undergo the transplant.
The night before treatment started, he was laughing and joking with a friend in his room at MSKCC. The next day, the laughing stopped. The conditioning, he said, “was harrowing beyond belief ... 100 times worse than the chemo.”
Chemotherapy came first, followed 2 days later by radiation, presumably TNI. Mr. Unger experienced constant vomiting, intraocular bleeding and high fevers; the soft tissue of his throat “fell apart,” he said.
“I couldn’t move. It was like being dead,” he said. “Finally, maybe after a month or so, I could finally have a little water.” Mr. Unger said his immune system took 6-8 weeks to recover. He concluded, with heroic understatement, “it was rough.”
The battle against Hodgkin was over, but fallout from the chemotherapy lingered. Although Mr. Unger was able to return to his family and the job he loved, in the following years he was never entirely well. He contracted shingles soon after his transplant, then diabetes within 15 years. A heart attack followed in 2008 then, in 2015, an autoimmune disease that still affects his mobility.
However, Mr. Unger remains grateful: “The fact that we did these cutting-edge techniques with me got me to the point where – although I had some problems afterward, and I have problems now – it gave me well over 30 years of a really great life.”
“There are a lot of good doctors out there,” he added. “Some of them go to extraordinary lengths to help people. I try to do the same with the extra 30 years I’ve been given, try to be nice to people and make people feel good. I don’t really see any other reason to be on earth.”
Treatment for Hodgkin lymphoma: 2022
For a comparison of Mr. Unger’s experience with the current approach to Hodgkin lymphoma, this news organization spoke to Miguel-Angel Perales, MD, current chief of the adult bone marrow transplant service at MSKCC. Although Dr. Perales could not comment specifically on Mr. Unger’s case without his records, Dr. Perales was able to review the revolutions in treatment for all patients over the past 30 years.
Certainly, physicians no longer need to inflict a laparotomy on patients just to stage the disease, Dr. Perales said. “This sounds barbaric today. Nowadays we have PET scans.”
Another key change, Dr. Perales said, is in the up-front management of the disease.
For example, MOPP “is going back to the prehistory of chemotherapy,” Dr. Perales said. He was not surprised to learn that Mr. Unger later developed complications such as diabetes and heart disease.
“We’ve completely revolutionized the treatment,” Dr. Perales said. “We [now] use combinations that are much less toxic than MOPP, [and] we’re curing more patients up front.” Treatment is tailored by stage and the likelihood of response to therapy. Aggressive approaches are reserved for patients more likely to fail treatment.
Pretransplant conditioning has also changed for the better, with less toxicity and fewer long-term complications. Total body irradiation has “fallen by the wayside,” said Dr. Perales. Instead, patients get BEAM, a combination of carmustine, etoposide, cytarabine (Cytosar-U, Ara-C), and melphalan (Alkeran), 1 week before the transplant.
Perhaps the most profound change, which began in the 1990s shortly after Larry’s transplant, was that peripheral-blood stem cells gradually replaced bone marrow for both autologous and allogeneic transplant. In 2022, nearly all autologous transplants use peripheral-blood stem cells.
Instead of onerous bone-marrow aspiration in the operating room, the stem cells are collected from the patient’s blood. First, the patient’s bone marrow is hyperstimulated with high doses of filgrastim (G-CSF, Neupogen, Granix) for several days. Stem cells spill into the patient’s blood. Once blood is collected from the patient, the stem cells are separated and stored ready for the transplant. (In theory, stem cell products are “cancer free”; in practice there may be some contaminating cells, said Dr. Perales.)
Nowadays “transplanting” the stem cells back into the body bears no relation to what happened in 1992. The stem-cell infusion is typically an outpatient procedure, and one-third of patients may never be admitted to the hospital at all.
In contrast to Mr. Unger’s excruciating 8-week hospital stay, immune recovery currently takes 12-14 days, often entirely in the patient’s own home, with the option of extra filgrastim to speed things up.
Despite these profound changes, said Dr. Perales, the real quantum leap has occurred post transplant.
In 2015, a multinational team led by MSKCC’s Dr. Craig Moskowitz published a trial in the Lancet showing that brentuximab vedotin halved the risk of relapse after autologous transplantation in high-risk Hodgkin lymphoma patients versus placebo (hazard ratio, 0.57; P = .0013; n = 329). The CD30-directed antibody-drug conjugate was so successful that the placebo patients were encouraged to cross over into the treatment group; many of them were salvaged.
As a result, Dr. Perales said, brentuximab vedotin has now become the standard in high-risk Hodgkin patients following a transplant.
The checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) have also been “transformational” in Hodgkin lymphoma, Dr. Perales said. He explained that Hodgkin lymphoma is “exquisitely sensitive” to these therapies because the disease expresses high levels of the binding proteins for these drugs. This allows the immunotherapies to hit both the immune system and the disease.
Most cancers have response rates for checkpoint inhibitors below 40%, according to a recent analysis by Anas Younes, former chief of lymphoma at MSKCC, and his colleague Eri Matsuki, then a visiting fellow. By contrast, in Hodgkin lymphoma response to these drugs is 66%-87%.
Dr. Perales said: “It tells you how effective these drugs are, that we could move from somebody getting MOPP, which is like throwing a nuclear bomb at somebody, to a combination of two drugs that can easily be given out-patient and that have very little, if any, side effects.”
The future: No chemo, no transplants?
“One of the holy grails in Hodgkin would be if we could treat patients with the combination of a checkpoint inhibitor and brentuximab and what is being termed the ‘chemotherapy-free’ approach to Hodgkin disease,” said Dr. Perales.
What else remains to be done in the world of transplants for Hodgkin lymphoma?
Dr. Perales didn’t hesitate: “To eliminate the need for them. If we can have better targeted therapy up front that cures more patients, then we never even have to consider transplant. Basically, to put me out of work. I’m sure I’ll find other things to do.”
The current treatment of Hodgkin lymphoma “is really what we all consider one of the successes in oncology,” said Dr. Perales. “It’s a beautiful story.”
Dr. Perales reported receiving honoraria from numerous pharmaceutical companies; serves on data and safety monitoring boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serves on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.
At 32 years old, the world was at Larry Unger’s feet. He was vice president at one of Wall Street’s most successful investment management firms, selling mutual funds to more than 1,000 brokers across New York. His clients relied on him for good advice, great jokes, and superlative Yankees tickets. His recent memories included fraternity days at Cornell University and a Harvard law degree. His childhood on the Lower East Side was behind him. He had his own apartment and a beautiful girlfriend.
Then his back started hurting, and he was drenched in sweat at night. His physician suggested it was a basketball injury. Weeks of tests followed, and he changed doctors. Mr. Unger met with an oncologist at Memorial Sloan Kettering Cancer Center who wouldn’t let him go home after the appointment. The next day brought exploratory surgery and an answer to all the questions.
Mr. Unger was diagnosed with stage IIIB Hodgkin lymphoma.
Thirty years later, Mr. Unger credited his survival to the late Subhash Gulati, MD, PhD, then MSKCC’s director of stem cell transplantation. He still recalls Dr. Gulati’s words to him: “Radical situations call for radical solutions.” In 1992, that “radical solution” was an autologous bone-marrow transplant.
“Mr. Unger was a patient pioneer,” said Kenneth Offit, MD, another MSKCC oncologist who also cared for him at that time.
Transplantation for Hodgkin: The early 90s
Hodgkin lymphoma is fairly rare, accounting for just 0.5% of all cancers and 15% of lymphomas. It tends to target young, male adults like Mr. Unger. Today 88% of patients with Hodgkin survive at least 5 years.
When Dr. Gulati offered Mr. Unger his “radical solution” 3 decades ago, the idea of autologous bone marrow transplantation in Hodgkin lymphoma was not new. The first attempt appeared in the literature in the 1950s, but it was still unclear how patients could survive the procedure. It involved destroying the patient’s own immune system prior to the transplant, a huge risk in itself. Worse, the patient was pummeled with chemotherapy and/or radiation to clear out the cancerous bone marrow – a process called “conditioning.”
However, throughout the 1980s, MSKCC had been running clinical trials to perfect the conditioning mix, so by 1992 Dr. Gulati was well-placed to help Mr. Unger.
It is unclear what conditioning Mr. Unger received because his records were not made available. However, around the time that Mr. Unger underwent his transplant, Dr. Gulati and colleagues published the conditioning regimens in use at MSKCC. Patients with refractory or relapsed Hodgkin disease received a conditioning mix of total nodal irradiation (TNI), etoposide (Vepesid) and cyclophosphamide. Patients who had already been through radiotherapy were given carmustine instead of TNI.
In that early publication, Dr. Gulati and the MSKCC team reported 0 “toxic deaths” with the TNI mix, and at the 2-year point 75% of the patients were still alive (n = 28). Patients who had already received radiation treatment did less well, with 55% survival at 2 years, at a cost of 14% toxic deaths (n = 22).
Mr. Unger’s experience, 30 years ago
According to Mr. Unger, the initial treatment for his stage IIIB Hodgkin lymphoma was MOPP (mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, and prednisone) plus ABVD (doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine).
“They wanted to give me two chemo programs at once because they said I was very sick,” Mr. Unger recalled. “I wound up staying in the hospital quite a bit because every time I got these [treatments] I’d get a fever. This went on for month after month after month. Finally, they said: ‘The tumors are starting to shrink. ... I want you to meet Dr. Gulati.’ ”
Mr. Unger said that Dr. Gulati told him: “There is another procedure called the bone marrow transplant which we’ve been doing. This would be like hitting it with a nuclear weapon. We would really wipe it out and make sure that you never come back.”
The alternative was high-dose radiotherapy. However, Dr. Gulati shared MSKCC’s hard-won knowledge that an autologous transplant was less successful after radiation. Dr. Gulati also told Mr. Unger that surgery was needed before the transplant: a laparotomy to restage his tumors.
After discussing the situation with his father, Mr. Unger decided to undergo the transplant.
The night before treatment started, he was laughing and joking with a friend in his room at MSKCC. The next day, the laughing stopped. The conditioning, he said, “was harrowing beyond belief ... 100 times worse than the chemo.”
Chemotherapy came first, followed 2 days later by radiation, presumably TNI. Mr. Unger experienced constant vomiting, intraocular bleeding and high fevers; the soft tissue of his throat “fell apart,” he said.
“I couldn’t move. It was like being dead,” he said. “Finally, maybe after a month or so, I could finally have a little water.” Mr. Unger said his immune system took 6-8 weeks to recover. He concluded, with heroic understatement, “it was rough.”
The battle against Hodgkin was over, but fallout from the chemotherapy lingered. Although Mr. Unger was able to return to his family and the job he loved, in the following years he was never entirely well. He contracted shingles soon after his transplant, then diabetes within 15 years. A heart attack followed in 2008 then, in 2015, an autoimmune disease that still affects his mobility.
However, Mr. Unger remains grateful: “The fact that we did these cutting-edge techniques with me got me to the point where – although I had some problems afterward, and I have problems now – it gave me well over 30 years of a really great life.”
“There are a lot of good doctors out there,” he added. “Some of them go to extraordinary lengths to help people. I try to do the same with the extra 30 years I’ve been given, try to be nice to people and make people feel good. I don’t really see any other reason to be on earth.”
Treatment for Hodgkin lymphoma: 2022
For a comparison of Mr. Unger’s experience with the current approach to Hodgkin lymphoma, this news organization spoke to Miguel-Angel Perales, MD, current chief of the adult bone marrow transplant service at MSKCC. Although Dr. Perales could not comment specifically on Mr. Unger’s case without his records, Dr. Perales was able to review the revolutions in treatment for all patients over the past 30 years.
Certainly, physicians no longer need to inflict a laparotomy on patients just to stage the disease, Dr. Perales said. “This sounds barbaric today. Nowadays we have PET scans.”
Another key change, Dr. Perales said, is in the up-front management of the disease.
For example, MOPP “is going back to the prehistory of chemotherapy,” Dr. Perales said. He was not surprised to learn that Mr. Unger later developed complications such as diabetes and heart disease.
“We’ve completely revolutionized the treatment,” Dr. Perales said. “We [now] use combinations that are much less toxic than MOPP, [and] we’re curing more patients up front.” Treatment is tailored by stage and the likelihood of response to therapy. Aggressive approaches are reserved for patients more likely to fail treatment.
Pretransplant conditioning has also changed for the better, with less toxicity and fewer long-term complications. Total body irradiation has “fallen by the wayside,” said Dr. Perales. Instead, patients get BEAM, a combination of carmustine, etoposide, cytarabine (Cytosar-U, Ara-C), and melphalan (Alkeran), 1 week before the transplant.
Perhaps the most profound change, which began in the 1990s shortly after Larry’s transplant, was that peripheral-blood stem cells gradually replaced bone marrow for both autologous and allogeneic transplant. In 2022, nearly all autologous transplants use peripheral-blood stem cells.
Instead of onerous bone-marrow aspiration in the operating room, the stem cells are collected from the patient’s blood. First, the patient’s bone marrow is hyperstimulated with high doses of filgrastim (G-CSF, Neupogen, Granix) for several days. Stem cells spill into the patient’s blood. Once blood is collected from the patient, the stem cells are separated and stored ready for the transplant. (In theory, stem cell products are “cancer free”; in practice there may be some contaminating cells, said Dr. Perales.)
Nowadays “transplanting” the stem cells back into the body bears no relation to what happened in 1992. The stem-cell infusion is typically an outpatient procedure, and one-third of patients may never be admitted to the hospital at all.
In contrast to Mr. Unger’s excruciating 8-week hospital stay, immune recovery currently takes 12-14 days, often entirely in the patient’s own home, with the option of extra filgrastim to speed things up.
Despite these profound changes, said Dr. Perales, the real quantum leap has occurred post transplant.
In 2015, a multinational team led by MSKCC’s Dr. Craig Moskowitz published a trial in the Lancet showing that brentuximab vedotin halved the risk of relapse after autologous transplantation in high-risk Hodgkin lymphoma patients versus placebo (hazard ratio, 0.57; P = .0013; n = 329). The CD30-directed antibody-drug conjugate was so successful that the placebo patients were encouraged to cross over into the treatment group; many of them were salvaged.
As a result, Dr. Perales said, brentuximab vedotin has now become the standard in high-risk Hodgkin patients following a transplant.
The checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) have also been “transformational” in Hodgkin lymphoma, Dr. Perales said. He explained that Hodgkin lymphoma is “exquisitely sensitive” to these therapies because the disease expresses high levels of the binding proteins for these drugs. This allows the immunotherapies to hit both the immune system and the disease.
Most cancers have response rates for checkpoint inhibitors below 40%, according to a recent analysis by Anas Younes, former chief of lymphoma at MSKCC, and his colleague Eri Matsuki, then a visiting fellow. By contrast, in Hodgkin lymphoma response to these drugs is 66%-87%.
Dr. Perales said: “It tells you how effective these drugs are, that we could move from somebody getting MOPP, which is like throwing a nuclear bomb at somebody, to a combination of two drugs that can easily be given out-patient and that have very little, if any, side effects.”
The future: No chemo, no transplants?
“One of the holy grails in Hodgkin would be if we could treat patients with the combination of a checkpoint inhibitor and brentuximab and what is being termed the ‘chemotherapy-free’ approach to Hodgkin disease,” said Dr. Perales.
What else remains to be done in the world of transplants for Hodgkin lymphoma?
Dr. Perales didn’t hesitate: “To eliminate the need for them. If we can have better targeted therapy up front that cures more patients, then we never even have to consider transplant. Basically, to put me out of work. I’m sure I’ll find other things to do.”
The current treatment of Hodgkin lymphoma “is really what we all consider one of the successes in oncology,” said Dr. Perales. “It’s a beautiful story.”
Dr. Perales reported receiving honoraria from numerous pharmaceutical companies; serves on data and safety monitoring boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serves on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.
Some leukemias detectable up to 16 years before diagnosis?
Previous analyses showed that monoclonal B-cell lymphocytosis (MBL), a CLL precursor state, has been detected up to 6 years before CLL diagnosis, the investigators explained, noting that “[a]nother prognostically relevant immunogenetic feature of CLL concerns the stereotype of the B-cell receptor immunoglobulins (BcR IG).”
“Indeed, distinct stereotyped subsets can be defined by the expression of shared sequence motifs and are associated with particular presentation and outcomes,” P. Martijn Kolijn, PhD, a researcher in the department of immunology at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues wrote in a brief report published online in Blood. In an effort to “gain insight into the composition of the BcR IG repertoire during the early stages of CLL,” the investigators utilized next-generation sequencing to analyze 124 blood samples taken from healthy individuals up to 22 years before they received a diagnosis of CLL or small lymphocytic leukemia (SLL). An additional 118 matched control samples were also analyzed.
Study subjects were participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
“First, unsurprisingly, we observed a significant difference in the frequency of the dominant clonotype in CLL patients versus controls with a median frequency of 54.9%, compared to only 0.38% in controls,” they wrote.
Among 28 patients whose lymphocyte counts were measured at baseline, 10 showed evidence of lymphocytosis up to 8 years before CLL diagnosis.
This suggests undiagnosed instances of high-count MBL (cases with a cell count above 0.5x 109 cells/L, which can progress to CLL) or asymptomatic CLL, they explained.
“In contrast, next-generation sequencing results showed detectable skewing of the IGH gene repertoire in 21/28 patients up to 15 years before CLL diagnosis, often in the absence of elevated lymphocyte counts,” they wrote. “Remarkably, some patients with CLL requiring treatment and clinical transformation to an aggressive B-cell lymphoma displayed considerable skewing in the IGH gene repertoire even 16 years before CLL diagnosis.”
Patients with a prediagnostic IGHV-unmutated dominant clonotype had significantly shorter overall survival after CLL diagnosis than did those with an IGHV-mutated clonotype, they noted.
“Furthermore, at early timepoints (>10 years before diagnosis), patients with a high dominant clonotype frequency were more likely to be IGHV mutated, whereas closer to diagnosis this tendency was lost, indicating that the prediagnostic phase may be even longer than 16 years for [mutated] CLL patients,” they added.
The investigators also found that:
- Twenty-five patients carried stereotyped BcR IG up to 17 years prior to CLL diagnosis, and of these, 10 clonotypes were assigned to minor subsets and 15 to major CLL subsets. Among the latter, 14 of the 15 belonged to high-risk subsets, and most of those showed a trend for faster disease evolution.
- High frequency of the dominant clonotype was evident in samples obtained less than 6 years before diagnosis, whereas high-risk stereotyped clonotypes found longer before diagnosis (as early as 16 years) tended to have a lower dominant clonotype frequency (<20% of IGH gene repertoire)
- The stereotyped BcR IG matched the clonotype at diagnosis for both patients with diagnostic material.
- No stereotyped subsets were identified among the dominant clonotypes of the healthy controls.
“To our knowledge, the dynamics of the emergence of biclonality in an MBL patient and subsequent progression to CLL have never been captured in such a convincing manner,” they noted.
The findings “extend current knowledge on the evolution of the IGH repertoire prior to CLL diagnosis, highlighting that even high-risk CLL subtypes may display a prolonged indolent preclinical stage,” they added, speculating that “somatic genetic aberrations, (auto)stimulation, epigenetic and/or microenvironmental influences are required for the transformation into overt CLL.”
The investigators also noted that since the observed skewing in the IGH gene repertoire often occurs prior to B-cell lymphocytosis, they consider the findings “a novel extension to the characterization of MBL.”
“Further studies may prove invaluable in the clinical distinction between ‘progressing’ MBL versus ‘stable’ MBL. Notwithstanding the above, we emphasize that early detection is only warranted if it provides clear benefits to patient care,” they concluded.
In a related commentary, Gerald Marti, MD, PhD, of the National Heart, Lung, and Blood Institute, emphasized that the findings “represent the earliest detection of a clonotypic precursor cell for CLL.” .
They also raise new questions and point to new directions for research, Dr. Marti noted.
“Where do we go from here? CLL has a long evolutionary history in which early branching may start as an oligoclonal process (antigen stimulation) and include driver mutations,” he wrote. “A long-term analysis of the B-cell repertoire in familial CLL might shed light on this process. Further clarification of the mechanisms of age-related immune senescence is also of interest.”
The study authors and Dr. Marti reported having no competing financial interests.
Previous analyses showed that monoclonal B-cell lymphocytosis (MBL), a CLL precursor state, has been detected up to 6 years before CLL diagnosis, the investigators explained, noting that “[a]nother prognostically relevant immunogenetic feature of CLL concerns the stereotype of the B-cell receptor immunoglobulins (BcR IG).”
“Indeed, distinct stereotyped subsets can be defined by the expression of shared sequence motifs and are associated with particular presentation and outcomes,” P. Martijn Kolijn, PhD, a researcher in the department of immunology at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues wrote in a brief report published online in Blood. In an effort to “gain insight into the composition of the BcR IG repertoire during the early stages of CLL,” the investigators utilized next-generation sequencing to analyze 124 blood samples taken from healthy individuals up to 22 years before they received a diagnosis of CLL or small lymphocytic leukemia (SLL). An additional 118 matched control samples were also analyzed.
Study subjects were participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
“First, unsurprisingly, we observed a significant difference in the frequency of the dominant clonotype in CLL patients versus controls with a median frequency of 54.9%, compared to only 0.38% in controls,” they wrote.
Among 28 patients whose lymphocyte counts were measured at baseline, 10 showed evidence of lymphocytosis up to 8 years before CLL diagnosis.
This suggests undiagnosed instances of high-count MBL (cases with a cell count above 0.5x 109 cells/L, which can progress to CLL) or asymptomatic CLL, they explained.
“In contrast, next-generation sequencing results showed detectable skewing of the IGH gene repertoire in 21/28 patients up to 15 years before CLL diagnosis, often in the absence of elevated lymphocyte counts,” they wrote. “Remarkably, some patients with CLL requiring treatment and clinical transformation to an aggressive B-cell lymphoma displayed considerable skewing in the IGH gene repertoire even 16 years before CLL diagnosis.”
Patients with a prediagnostic IGHV-unmutated dominant clonotype had significantly shorter overall survival after CLL diagnosis than did those with an IGHV-mutated clonotype, they noted.
“Furthermore, at early timepoints (>10 years before diagnosis), patients with a high dominant clonotype frequency were more likely to be IGHV mutated, whereas closer to diagnosis this tendency was lost, indicating that the prediagnostic phase may be even longer than 16 years for [mutated] CLL patients,” they added.
The investigators also found that:
- Twenty-five patients carried stereotyped BcR IG up to 17 years prior to CLL diagnosis, and of these, 10 clonotypes were assigned to minor subsets and 15 to major CLL subsets. Among the latter, 14 of the 15 belonged to high-risk subsets, and most of those showed a trend for faster disease evolution.
- High frequency of the dominant clonotype was evident in samples obtained less than 6 years before diagnosis, whereas high-risk stereotyped clonotypes found longer before diagnosis (as early as 16 years) tended to have a lower dominant clonotype frequency (<20% of IGH gene repertoire)
- The stereotyped BcR IG matched the clonotype at diagnosis for both patients with diagnostic material.
- No stereotyped subsets were identified among the dominant clonotypes of the healthy controls.
“To our knowledge, the dynamics of the emergence of biclonality in an MBL patient and subsequent progression to CLL have never been captured in such a convincing manner,” they noted.
The findings “extend current knowledge on the evolution of the IGH repertoire prior to CLL diagnosis, highlighting that even high-risk CLL subtypes may display a prolonged indolent preclinical stage,” they added, speculating that “somatic genetic aberrations, (auto)stimulation, epigenetic and/or microenvironmental influences are required for the transformation into overt CLL.”
The investigators also noted that since the observed skewing in the IGH gene repertoire often occurs prior to B-cell lymphocytosis, they consider the findings “a novel extension to the characterization of MBL.”
“Further studies may prove invaluable in the clinical distinction between ‘progressing’ MBL versus ‘stable’ MBL. Notwithstanding the above, we emphasize that early detection is only warranted if it provides clear benefits to patient care,” they concluded.
In a related commentary, Gerald Marti, MD, PhD, of the National Heart, Lung, and Blood Institute, emphasized that the findings “represent the earliest detection of a clonotypic precursor cell for CLL.” .
They also raise new questions and point to new directions for research, Dr. Marti noted.
“Where do we go from here? CLL has a long evolutionary history in which early branching may start as an oligoclonal process (antigen stimulation) and include driver mutations,” he wrote. “A long-term analysis of the B-cell repertoire in familial CLL might shed light on this process. Further clarification of the mechanisms of age-related immune senescence is also of interest.”
The study authors and Dr. Marti reported having no competing financial interests.
Previous analyses showed that monoclonal B-cell lymphocytosis (MBL), a CLL precursor state, has been detected up to 6 years before CLL diagnosis, the investigators explained, noting that “[a]nother prognostically relevant immunogenetic feature of CLL concerns the stereotype of the B-cell receptor immunoglobulins (BcR IG).”
“Indeed, distinct stereotyped subsets can be defined by the expression of shared sequence motifs and are associated with particular presentation and outcomes,” P. Martijn Kolijn, PhD, a researcher in the department of immunology at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues wrote in a brief report published online in Blood. In an effort to “gain insight into the composition of the BcR IG repertoire during the early stages of CLL,” the investigators utilized next-generation sequencing to analyze 124 blood samples taken from healthy individuals up to 22 years before they received a diagnosis of CLL or small lymphocytic leukemia (SLL). An additional 118 matched control samples were also analyzed.
Study subjects were participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
“First, unsurprisingly, we observed a significant difference in the frequency of the dominant clonotype in CLL patients versus controls with a median frequency of 54.9%, compared to only 0.38% in controls,” they wrote.
Among 28 patients whose lymphocyte counts were measured at baseline, 10 showed evidence of lymphocytosis up to 8 years before CLL diagnosis.
This suggests undiagnosed instances of high-count MBL (cases with a cell count above 0.5x 109 cells/L, which can progress to CLL) or asymptomatic CLL, they explained.
“In contrast, next-generation sequencing results showed detectable skewing of the IGH gene repertoire in 21/28 patients up to 15 years before CLL diagnosis, often in the absence of elevated lymphocyte counts,” they wrote. “Remarkably, some patients with CLL requiring treatment and clinical transformation to an aggressive B-cell lymphoma displayed considerable skewing in the IGH gene repertoire even 16 years before CLL diagnosis.”
Patients with a prediagnostic IGHV-unmutated dominant clonotype had significantly shorter overall survival after CLL diagnosis than did those with an IGHV-mutated clonotype, they noted.
“Furthermore, at early timepoints (>10 years before diagnosis), patients with a high dominant clonotype frequency were more likely to be IGHV mutated, whereas closer to diagnosis this tendency was lost, indicating that the prediagnostic phase may be even longer than 16 years for [mutated] CLL patients,” they added.
The investigators also found that:
- Twenty-five patients carried stereotyped BcR IG up to 17 years prior to CLL diagnosis, and of these, 10 clonotypes were assigned to minor subsets and 15 to major CLL subsets. Among the latter, 14 of the 15 belonged to high-risk subsets, and most of those showed a trend for faster disease evolution.
- High frequency of the dominant clonotype was evident in samples obtained less than 6 years before diagnosis, whereas high-risk stereotyped clonotypes found longer before diagnosis (as early as 16 years) tended to have a lower dominant clonotype frequency (<20% of IGH gene repertoire)
- The stereotyped BcR IG matched the clonotype at diagnosis for both patients with diagnostic material.
- No stereotyped subsets were identified among the dominant clonotypes of the healthy controls.
“To our knowledge, the dynamics of the emergence of biclonality in an MBL patient and subsequent progression to CLL have never been captured in such a convincing manner,” they noted.
The findings “extend current knowledge on the evolution of the IGH repertoire prior to CLL diagnosis, highlighting that even high-risk CLL subtypes may display a prolonged indolent preclinical stage,” they added, speculating that “somatic genetic aberrations, (auto)stimulation, epigenetic and/or microenvironmental influences are required for the transformation into overt CLL.”
The investigators also noted that since the observed skewing in the IGH gene repertoire often occurs prior to B-cell lymphocytosis, they consider the findings “a novel extension to the characterization of MBL.”
“Further studies may prove invaluable in the clinical distinction between ‘progressing’ MBL versus ‘stable’ MBL. Notwithstanding the above, we emphasize that early detection is only warranted if it provides clear benefits to patient care,” they concluded.
In a related commentary, Gerald Marti, MD, PhD, of the National Heart, Lung, and Blood Institute, emphasized that the findings “represent the earliest detection of a clonotypic precursor cell for CLL.” .
They also raise new questions and point to new directions for research, Dr. Marti noted.
“Where do we go from here? CLL has a long evolutionary history in which early branching may start as an oligoclonal process (antigen stimulation) and include driver mutations,” he wrote. “A long-term analysis of the B-cell repertoire in familial CLL might shed light on this process. Further clarification of the mechanisms of age-related immune senescence is also of interest.”
The study authors and Dr. Marti reported having no competing financial interests.
FROM BLOOD
A little-known offshoot of hem/onc opens pathway for professional development
Only a small number of pediatric hematologist oncologists and even fewer of our adult counterparts feel comfortable evaluating and treating vascular anomalies.
While admittedly rare, these conditions are still common enough that clinicians in many disciplines encounter them. Hematologist/oncologists are most likely to see vascular malformations, which often present as mass lesions. Complications of these disorders occur across the hematology-oncology spectrum and include clots, pulmonary emboli, cancer predisposition, and an array of functional and psychosocial disorders.
Vascular anomalies are broadly categorized as vascular tumors or malformations. The tumors include hemangiomas, locally aggressive lesions, and true cancers. Malformations can be isolated disorders of one or more blood vessel types (veins, arteries, capillaries or lymphatics), or they can be one part of syndromic disorders. Lymphedema also falls under the heading of vascular anomalies. To make the terminology less confusing, in 2018 the International Society for the Study of Vascular Anomalies refined its classification scheme.
Vascular malformations are thought to be congenital. Although some are obvious at birth, others aren’t apparent until adulthood. In most cases, they grow with a child and may do so disproportionately at puberty and with pregnancies. The fact that vascular malformations persist into adulthood is one reason why their care should be integral to medical hematology-oncology.
Although the cause of a vascular malformation is not always known, a wide range of genetic mutations thought to be pathogenic have been reported. These mutations are usually somatic (only within the involved tissues, not in the blood or germ cells and therefore, not heritable) and tend to cluster in the VEGF-PIK3CA and RAS-MAP signaling pathways.
These genes and pathways will be familiar to any oncologist who cares for patients with solid tumors, notably breast cancer or melanoma. However, unlike the clonal expansion seen in cancers, most vascular malformations will express pathogenic mutations in less than 20% of vascular endothelium within a malformation.
Since 2008, medical management has been limited to sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, which can be effective even when mTOR mutations aren’t apparent. In a seminal phase 2 trial of 57 patients with complex vascular anomalies who were aged 0-29 years, 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. None had complete responses. These data highlight the need for more effective treatments.
Recently, vascular anomalists have begun to repurpose drugs from adult oncology that specifically target pathogenic mutations. Some studies underway include Novartis’ international Alpelisib (Piqray) clinical trial for adults and children with PIK3CA-related overgrowth syndromes (NCT04589650) and Merck’s follow-up study of the AKT inhibitor miransertib for PROS and Proteus syndrome. Doses tend to be lower than those used to treat cancers. To date, these have been generally well-tolerated, with sometimes striking but preliminary evidence of efficacy.
During the past 2 years, symposia on vascular anomalies at the annual meeting of the American Society of Hematology have launched what we are hoping is just the start of a broader discussion. In 2020, Fran Blei, MD, chaired Vascular Anomalies 101: Case-Based Discussion on the Diagnosis, Treatment and Lifelong Care of These Patients, and in 2021, Adrienne Hammill, MD, PhD, and Dr. Raj Kasthuri, MBBS, MD, chaired a more specialized symposium: Hereditary Hemorrhagic Telangiectasia (HHT): A Practical Guide to Management.
Dr. Blatt is in the division of pediatric hematology oncology at the University of North Carolina at Chapel Hill. She disclosed no relevant financial relationships.
Only a small number of pediatric hematologist oncologists and even fewer of our adult counterparts feel comfortable evaluating and treating vascular anomalies.
While admittedly rare, these conditions are still common enough that clinicians in many disciplines encounter them. Hematologist/oncologists are most likely to see vascular malformations, which often present as mass lesions. Complications of these disorders occur across the hematology-oncology spectrum and include clots, pulmonary emboli, cancer predisposition, and an array of functional and psychosocial disorders.
Vascular anomalies are broadly categorized as vascular tumors or malformations. The tumors include hemangiomas, locally aggressive lesions, and true cancers. Malformations can be isolated disorders of one or more blood vessel types (veins, arteries, capillaries or lymphatics), or they can be one part of syndromic disorders. Lymphedema also falls under the heading of vascular anomalies. To make the terminology less confusing, in 2018 the International Society for the Study of Vascular Anomalies refined its classification scheme.
Vascular malformations are thought to be congenital. Although some are obvious at birth, others aren’t apparent until adulthood. In most cases, they grow with a child and may do so disproportionately at puberty and with pregnancies. The fact that vascular malformations persist into adulthood is one reason why their care should be integral to medical hematology-oncology.
Although the cause of a vascular malformation is not always known, a wide range of genetic mutations thought to be pathogenic have been reported. These mutations are usually somatic (only within the involved tissues, not in the blood or germ cells and therefore, not heritable) and tend to cluster in the VEGF-PIK3CA and RAS-MAP signaling pathways.
These genes and pathways will be familiar to any oncologist who cares for patients with solid tumors, notably breast cancer or melanoma. However, unlike the clonal expansion seen in cancers, most vascular malformations will express pathogenic mutations in less than 20% of vascular endothelium within a malformation.
Since 2008, medical management has been limited to sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, which can be effective even when mTOR mutations aren’t apparent. In a seminal phase 2 trial of 57 patients with complex vascular anomalies who were aged 0-29 years, 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. None had complete responses. These data highlight the need for more effective treatments.
Recently, vascular anomalists have begun to repurpose drugs from adult oncology that specifically target pathogenic mutations. Some studies underway include Novartis’ international Alpelisib (Piqray) clinical trial for adults and children with PIK3CA-related overgrowth syndromes (NCT04589650) and Merck’s follow-up study of the AKT inhibitor miransertib for PROS and Proteus syndrome. Doses tend to be lower than those used to treat cancers. To date, these have been generally well-tolerated, with sometimes striking but preliminary evidence of efficacy.
During the past 2 years, symposia on vascular anomalies at the annual meeting of the American Society of Hematology have launched what we are hoping is just the start of a broader discussion. In 2020, Fran Blei, MD, chaired Vascular Anomalies 101: Case-Based Discussion on the Diagnosis, Treatment and Lifelong Care of These Patients, and in 2021, Adrienne Hammill, MD, PhD, and Dr. Raj Kasthuri, MBBS, MD, chaired a more specialized symposium: Hereditary Hemorrhagic Telangiectasia (HHT): A Practical Guide to Management.
Dr. Blatt is in the division of pediatric hematology oncology at the University of North Carolina at Chapel Hill. She disclosed no relevant financial relationships.
Only a small number of pediatric hematologist oncologists and even fewer of our adult counterparts feel comfortable evaluating and treating vascular anomalies.
While admittedly rare, these conditions are still common enough that clinicians in many disciplines encounter them. Hematologist/oncologists are most likely to see vascular malformations, which often present as mass lesions. Complications of these disorders occur across the hematology-oncology spectrum and include clots, pulmonary emboli, cancer predisposition, and an array of functional and psychosocial disorders.
Vascular anomalies are broadly categorized as vascular tumors or malformations. The tumors include hemangiomas, locally aggressive lesions, and true cancers. Malformations can be isolated disorders of one or more blood vessel types (veins, arteries, capillaries or lymphatics), or they can be one part of syndromic disorders. Lymphedema also falls under the heading of vascular anomalies. To make the terminology less confusing, in 2018 the International Society for the Study of Vascular Anomalies refined its classification scheme.
Vascular malformations are thought to be congenital. Although some are obvious at birth, others aren’t apparent until adulthood. In most cases, they grow with a child and may do so disproportionately at puberty and with pregnancies. The fact that vascular malformations persist into adulthood is one reason why their care should be integral to medical hematology-oncology.
Although the cause of a vascular malformation is not always known, a wide range of genetic mutations thought to be pathogenic have been reported. These mutations are usually somatic (only within the involved tissues, not in the blood or germ cells and therefore, not heritable) and tend to cluster in the VEGF-PIK3CA and RAS-MAP signaling pathways.
These genes and pathways will be familiar to any oncologist who cares for patients with solid tumors, notably breast cancer or melanoma. However, unlike the clonal expansion seen in cancers, most vascular malformations will express pathogenic mutations in less than 20% of vascular endothelium within a malformation.
Since 2008, medical management has been limited to sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, which can be effective even when mTOR mutations aren’t apparent. In a seminal phase 2 trial of 57 patients with complex vascular anomalies who were aged 0-29 years, 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. None had complete responses. These data highlight the need for more effective treatments.
Recently, vascular anomalists have begun to repurpose drugs from adult oncology that specifically target pathogenic mutations. Some studies underway include Novartis’ international Alpelisib (Piqray) clinical trial for adults and children with PIK3CA-related overgrowth syndromes (NCT04589650) and Merck’s follow-up study of the AKT inhibitor miransertib for PROS and Proteus syndrome. Doses tend to be lower than those used to treat cancers. To date, these have been generally well-tolerated, with sometimes striking but preliminary evidence of efficacy.
During the past 2 years, symposia on vascular anomalies at the annual meeting of the American Society of Hematology have launched what we are hoping is just the start of a broader discussion. In 2020, Fran Blei, MD, chaired Vascular Anomalies 101: Case-Based Discussion on the Diagnosis, Treatment and Lifelong Care of These Patients, and in 2021, Adrienne Hammill, MD, PhD, and Dr. Raj Kasthuri, MBBS, MD, chaired a more specialized symposium: Hereditary Hemorrhagic Telangiectasia (HHT): A Practical Guide to Management.
Dr. Blatt is in the division of pediatric hematology oncology at the University of North Carolina at Chapel Hill. She disclosed no relevant financial relationships.
Eating olive oil may slow CLL disease progression
Olive oil is a major component of the Mediterranean diet, and olive phenols have been shown to convey antioxidant, anti-inflammatory, anticancer, neuroprotective, and antidiabetic effects by modulating various molecular pathways, Andrea Paola Rojas Gil, PhD, of the University of Peloponnese, Tripoli, Greece, and colleagues wrote.
In most patients, CLL is incurable, but those at the early stages do not need immediate therapy and may benefit from an intervention to prevent disease progression, the authors wrote. Previous research suggested that dietary intervention exerts a salutary effect on early CLL, and in vitro studies suggested that oleocanthal, a component of extra virgin olive oil, induced anticancer activity.
In a study published in Frontiers in Oncology, the researchers enrolled adults with early stage CLL who had not undergone chemotherapy or other treatment. All patients adhered to a Mediterranean-style diet.
After a washout period of 9-12 months, the researchers randomized 22 patients to extra virgin olive oil high in oleocanthal and oleacein (high OC/OL-EVOO). Patients in the intervention group consumed 40 mL/day of high OC/OL-EVOO before meals. Their average age was 71 years; 10 were women and 12 were men.
The primary outcomes included changes in hematological, biochemical, and apoptotic markers. After 6 months, patients in the intervention group showed a statistically significant reduction in white blood cells and lymphocyte count, compared with measurements taken 3 months before the intervention. The WBC decrease was greatest among patients with the highest WBC levels at baseline.
As for biochemical markers, the researchers observed a significant decrease in glucose levels during the intervention, but no significant effects on metabolic indexes or renal function.
After 3 months and also after 6 months of the olive oil intervention, patients showed a significant increase in the apoptotic markers ccK18 and Apo1-Fas (P ≤ .05 for both), as well as an increase in the cell cycle negative regulator p21. The dietary intervention also was associated with significant decreases in expression of the antiapoptotic protein survivin and in cyclin D, a positive cell cycle regulator protein.
Further, patients who had a high ccK18 level at baseline showed a significantly greater increase in ccK18 after the intervention, compared with those with lower ccK18 at baseline (P = .001).
Notably, “a negative correlation of the WBC at the end of the dietary intervention with the fluctuation of the protein expression of the apoptotic marker ccK18 (final – initial) was observed,” the researchers wrote in their discussion.
The study findings were limited by several factors including the small sample size, short intervention time, and pilot design, the researchers said. Other limitations include the possible effect of other unmeasured properties of olive oil.
However, the results reflect previous studies showing the benefits of a Mediterranean-type diet, and they represent the first clinical trial to indicate possible beneficial effects from oleocanthal and oleacein on the progression of CLL. Therefore, the authors concluded, the study is worthy of a large, multicenter trial.
Pilot data merit more research
In an interview, corresponding author Prokopios Magiatis, PhD, noted that CLL is “the most commonly diagnosed adult leukemia in Western countries and is responsible for about one in four cases of all leukemias.” CLL remains incurable in most patients, and ways to delay disease progression are needed.
“Oleocanthal is the active ingredient of early harvest olive oil with proven anticancer activities in vitro and in vivo,” Dr. Magiatis explained. “For this reason, it was a unique challenge to investigate the anticancer activity of this compound for the first time in humans through the dietary consumption of specifically selected olive oil.” He expressed surprise at the beneficial effects of high-oleocanthal olive oil, not only to the white blood cells, but also to glucose levels.
“It seems that oleocanthal can activate mechanisms related to the apoptosis of cancer cells, and also mechanisms related to blood glucose regulation without affecting any normal cells of the body,” he said. “All anticancer drugs usually have severe side effects, however the administration of 25 mg of oleocanthal through the dietary consumption of olive oil did not present any harmful effects for at least 6 months of everyday use.
“The addition of naturally produced high-oleocanthal olive oil in the diet of early-stage CLL patients at a dose of three tablespoons per day [40 mL] is a practice that may lower the cancerous white blood cells of the patients without any risk,” said Dr. Magiatis. “High-oleocanthal early-harvest olive oil has been consumed for centuries, and may be the key of longevity of several Mediterranean populations.
“In our study, the number of the white blood cells returned back to the number it was one year before the initiation of the study; this clearly shows that it could be a significant factor for the delay of the progress of the disease,” he said.
The current trial was a pilot study in one hospital with only 22 patients for 6 months, said Dr. Magiatis. “We are currently preparing the expansion of the study to other hospitals and other countries, and we aim to include at least 100 patients for at least 1 year, to validate the already-obtained beneficial results.”
The clinical trial is supported by the nonprofit organization World Olive Center for Health, he added.
The current study received no outside funding. The researchers had no financial conflicts to disclose.
Olive oil is a major component of the Mediterranean diet, and olive phenols have been shown to convey antioxidant, anti-inflammatory, anticancer, neuroprotective, and antidiabetic effects by modulating various molecular pathways, Andrea Paola Rojas Gil, PhD, of the University of Peloponnese, Tripoli, Greece, and colleagues wrote.
In most patients, CLL is incurable, but those at the early stages do not need immediate therapy and may benefit from an intervention to prevent disease progression, the authors wrote. Previous research suggested that dietary intervention exerts a salutary effect on early CLL, and in vitro studies suggested that oleocanthal, a component of extra virgin olive oil, induced anticancer activity.
In a study published in Frontiers in Oncology, the researchers enrolled adults with early stage CLL who had not undergone chemotherapy or other treatment. All patients adhered to a Mediterranean-style diet.
After a washout period of 9-12 months, the researchers randomized 22 patients to extra virgin olive oil high in oleocanthal and oleacein (high OC/OL-EVOO). Patients in the intervention group consumed 40 mL/day of high OC/OL-EVOO before meals. Their average age was 71 years; 10 were women and 12 were men.
The primary outcomes included changes in hematological, biochemical, and apoptotic markers. After 6 months, patients in the intervention group showed a statistically significant reduction in white blood cells and lymphocyte count, compared with measurements taken 3 months before the intervention. The WBC decrease was greatest among patients with the highest WBC levels at baseline.
As for biochemical markers, the researchers observed a significant decrease in glucose levels during the intervention, but no significant effects on metabolic indexes or renal function.
After 3 months and also after 6 months of the olive oil intervention, patients showed a significant increase in the apoptotic markers ccK18 and Apo1-Fas (P ≤ .05 for both), as well as an increase in the cell cycle negative regulator p21. The dietary intervention also was associated with significant decreases in expression of the antiapoptotic protein survivin and in cyclin D, a positive cell cycle regulator protein.
Further, patients who had a high ccK18 level at baseline showed a significantly greater increase in ccK18 after the intervention, compared with those with lower ccK18 at baseline (P = .001).
Notably, “a negative correlation of the WBC at the end of the dietary intervention with the fluctuation of the protein expression of the apoptotic marker ccK18 (final – initial) was observed,” the researchers wrote in their discussion.
The study findings were limited by several factors including the small sample size, short intervention time, and pilot design, the researchers said. Other limitations include the possible effect of other unmeasured properties of olive oil.
However, the results reflect previous studies showing the benefits of a Mediterranean-type diet, and they represent the first clinical trial to indicate possible beneficial effects from oleocanthal and oleacein on the progression of CLL. Therefore, the authors concluded, the study is worthy of a large, multicenter trial.
Pilot data merit more research
In an interview, corresponding author Prokopios Magiatis, PhD, noted that CLL is “the most commonly diagnosed adult leukemia in Western countries and is responsible for about one in four cases of all leukemias.” CLL remains incurable in most patients, and ways to delay disease progression are needed.
“Oleocanthal is the active ingredient of early harvest olive oil with proven anticancer activities in vitro and in vivo,” Dr. Magiatis explained. “For this reason, it was a unique challenge to investigate the anticancer activity of this compound for the first time in humans through the dietary consumption of specifically selected olive oil.” He expressed surprise at the beneficial effects of high-oleocanthal olive oil, not only to the white blood cells, but also to glucose levels.
“It seems that oleocanthal can activate mechanisms related to the apoptosis of cancer cells, and also mechanisms related to blood glucose regulation without affecting any normal cells of the body,” he said. “All anticancer drugs usually have severe side effects, however the administration of 25 mg of oleocanthal through the dietary consumption of olive oil did not present any harmful effects for at least 6 months of everyday use.
“The addition of naturally produced high-oleocanthal olive oil in the diet of early-stage CLL patients at a dose of three tablespoons per day [40 mL] is a practice that may lower the cancerous white blood cells of the patients without any risk,” said Dr. Magiatis. “High-oleocanthal early-harvest olive oil has been consumed for centuries, and may be the key of longevity of several Mediterranean populations.
“In our study, the number of the white blood cells returned back to the number it was one year before the initiation of the study; this clearly shows that it could be a significant factor for the delay of the progress of the disease,” he said.
The current trial was a pilot study in one hospital with only 22 patients for 6 months, said Dr. Magiatis. “We are currently preparing the expansion of the study to other hospitals and other countries, and we aim to include at least 100 patients for at least 1 year, to validate the already-obtained beneficial results.”
The clinical trial is supported by the nonprofit organization World Olive Center for Health, he added.
The current study received no outside funding. The researchers had no financial conflicts to disclose.
Olive oil is a major component of the Mediterranean diet, and olive phenols have been shown to convey antioxidant, anti-inflammatory, anticancer, neuroprotective, and antidiabetic effects by modulating various molecular pathways, Andrea Paola Rojas Gil, PhD, of the University of Peloponnese, Tripoli, Greece, and colleagues wrote.
In most patients, CLL is incurable, but those at the early stages do not need immediate therapy and may benefit from an intervention to prevent disease progression, the authors wrote. Previous research suggested that dietary intervention exerts a salutary effect on early CLL, and in vitro studies suggested that oleocanthal, a component of extra virgin olive oil, induced anticancer activity.
In a study published in Frontiers in Oncology, the researchers enrolled adults with early stage CLL who had not undergone chemotherapy or other treatment. All patients adhered to a Mediterranean-style diet.
After a washout period of 9-12 months, the researchers randomized 22 patients to extra virgin olive oil high in oleocanthal and oleacein (high OC/OL-EVOO). Patients in the intervention group consumed 40 mL/day of high OC/OL-EVOO before meals. Their average age was 71 years; 10 were women and 12 were men.
The primary outcomes included changes in hematological, biochemical, and apoptotic markers. After 6 months, patients in the intervention group showed a statistically significant reduction in white blood cells and lymphocyte count, compared with measurements taken 3 months before the intervention. The WBC decrease was greatest among patients with the highest WBC levels at baseline.
As for biochemical markers, the researchers observed a significant decrease in glucose levels during the intervention, but no significant effects on metabolic indexes or renal function.
After 3 months and also after 6 months of the olive oil intervention, patients showed a significant increase in the apoptotic markers ccK18 and Apo1-Fas (P ≤ .05 for both), as well as an increase in the cell cycle negative regulator p21. The dietary intervention also was associated with significant decreases in expression of the antiapoptotic protein survivin and in cyclin D, a positive cell cycle regulator protein.
Further, patients who had a high ccK18 level at baseline showed a significantly greater increase in ccK18 after the intervention, compared with those with lower ccK18 at baseline (P = .001).
Notably, “a negative correlation of the WBC at the end of the dietary intervention with the fluctuation of the protein expression of the apoptotic marker ccK18 (final – initial) was observed,” the researchers wrote in their discussion.
The study findings were limited by several factors including the small sample size, short intervention time, and pilot design, the researchers said. Other limitations include the possible effect of other unmeasured properties of olive oil.
However, the results reflect previous studies showing the benefits of a Mediterranean-type diet, and they represent the first clinical trial to indicate possible beneficial effects from oleocanthal and oleacein on the progression of CLL. Therefore, the authors concluded, the study is worthy of a large, multicenter trial.
Pilot data merit more research
In an interview, corresponding author Prokopios Magiatis, PhD, noted that CLL is “the most commonly diagnosed adult leukemia in Western countries and is responsible for about one in four cases of all leukemias.” CLL remains incurable in most patients, and ways to delay disease progression are needed.
“Oleocanthal is the active ingredient of early harvest olive oil with proven anticancer activities in vitro and in vivo,” Dr. Magiatis explained. “For this reason, it was a unique challenge to investigate the anticancer activity of this compound for the first time in humans through the dietary consumption of specifically selected olive oil.” He expressed surprise at the beneficial effects of high-oleocanthal olive oil, not only to the white blood cells, but also to glucose levels.
“It seems that oleocanthal can activate mechanisms related to the apoptosis of cancer cells, and also mechanisms related to blood glucose regulation without affecting any normal cells of the body,” he said. “All anticancer drugs usually have severe side effects, however the administration of 25 mg of oleocanthal through the dietary consumption of olive oil did not present any harmful effects for at least 6 months of everyday use.
“The addition of naturally produced high-oleocanthal olive oil in the diet of early-stage CLL patients at a dose of three tablespoons per day [40 mL] is a practice that may lower the cancerous white blood cells of the patients without any risk,” said Dr. Magiatis. “High-oleocanthal early-harvest olive oil has been consumed for centuries, and may be the key of longevity of several Mediterranean populations.
“In our study, the number of the white blood cells returned back to the number it was one year before the initiation of the study; this clearly shows that it could be a significant factor for the delay of the progress of the disease,” he said.
The current trial was a pilot study in one hospital with only 22 patients for 6 months, said Dr. Magiatis. “We are currently preparing the expansion of the study to other hospitals and other countries, and we aim to include at least 100 patients for at least 1 year, to validate the already-obtained beneficial results.”
The clinical trial is supported by the nonprofit organization World Olive Center for Health, he added.
The current study received no outside funding. The researchers had no financial conflicts to disclose.
FROM FRONTIERS IN ONCOLOGY
Repurposed drug could revolutionize stem cell transplantation
When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.
Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.
Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.
Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).
Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)
A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).
The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
Could abatacept fuel greater use of mismatched, unrelated donors?
One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.
Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.
Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.
Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.
“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.
That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
Further study of abatacept
With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.
Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”
Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”
Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”
Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.
When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.
Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.
Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.
Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).
Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)
A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).
The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
Could abatacept fuel greater use of mismatched, unrelated donors?
One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.
Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.
Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.
Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.
“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.
That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
Further study of abatacept
With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.
Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”
Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”
Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”
Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.
When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.
Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.
Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.
Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).
Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)
A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).
The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
Could abatacept fuel greater use of mismatched, unrelated donors?
One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.
Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.
Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.
Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.
“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.
That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
Further study of abatacept
With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.
Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”
Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”
Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”
Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.
Hodgkin-directed therapy may benefit patients with rare CLL subtype
Patients who have a rare subtype of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with isolated Hodgkin/Reed–Sternberg-like cells (CLL-HRS) may benefit from Hodgkin-directed therapy, based on data from 46 individuals.
Those patients who progress to classic Hodgkin lymphoma (CHL) from CLL/SLL are generally diagnosed based on straightforward pathology and treated with HRS cells in the same way as patients with de novo CHL, wrote lead author Dr. Rebecca L. King, a pathologist at the Mayo Clinic in Rochester, Minn.
Given the rarity of CLL-HRS, data on patient management are limited, they noted.
In a retrospective study published in Blood Cancer Journal, researchers reviewed outcome data from 15 adults with CLL-HRS and 31 adults with CLL/SLL who had overtly transformed to CLL-HL. The median age of the participants at the time of CLL-HL or CLL-HRS transformation diagnosis was 72 years; 71% and 87% of the CLL-HL and CLL-HRS patients, respectively, were male.
The median times from CLL to CLL-HL transformation and from CLL to CLL-HRS transformation were 6.6 years and 4.9 years, respectively; the difference was not statistically significant. The phenotypic features of Reed-Sternberg cells and Epstein-Barr virus status were similar in both patient groups. Two patients had biopsies in which both CLL-HRS and CLL-HL were present in the same tissue at initial diagnosis; they were included in the CLL-HL group for clinical analysis and in both groups for pathology analysis.
The median overall survival of CLL-HRS patients was 17.5 months, compared with 33.5 months for CLL-HL patients (P = .24), a nonsignificant difference. However, patients with CLL-HRS who received Hodgkin-directed therapy had a significantly longer median overall survival, compared with those who received CLL-directed therapy (57 months vs. 8.4 months, P = .02).
CLL-directed therapy included rituximab with or without corticosteroids, chemoimmunotherapy, or acalabrutinib; HL-directed therapy included doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine–based treatment; radiotherapy; or BCVPP (carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone).
Histopathology findings showed that CLL-HL patients had a background of mixed inflammation that was distinct from findings in CLL/SLL. CLL-HRS patients had a minimal inflammatory background, compared with CLL-HL cases, but researchers identified rosetting of T cells around the HRS cells in 56% of these patients.
“Our findings suggest that, clinically and pathologically, these patients show a spectrum of findings, and these two entities likely exist on a biologic continuum. Furthermore, our findings suggest that CLL-HRS patients managed with Hodgkin-directed therapy, rather than CLL-directed therapy, may have superior outcomes,” the researchers wrote.
The study findings were limited by several factors, including the retrospective design and the use of data from a single center. Therefore, the results should be validated in other cohorts, the researchers noted. In addition, the study participants were diagnosed over three decades, and management of the condition has significantly improved.
However, the results were strengthened by a review of data by three pathologists who were blinded to the clinical outcomes, they said.
“These findings have important implications for a scenario in which clinical guidelines are lacking and suggest that hematologists treating patients with CLL-HRS should consider HL-directed therapy,” the researchers concluded.
In an interview, Jennifer A. Woyach, MD, a hematologist at Ohio State University, Columbus, commented on the study findings: “Hodgkin transformation and CLL with Hodgkin-like cells likely represent a biologic continuum, and care should be taken to obtain adequate biopsies, so that the diagnosis of Hodgkin transformation can be made when appropriate.”
“Interestingly, the authors noted a trend toward improved survival when CLL with Hodgkin-like cells was treated with standard Hodgkin regimens,” said Dr. Woyach. “With the small patient numbers, this certainly cannot be a general recommendation, but should be considered by treating physicians on a case-by-case basis.”
“While we know that patients with Hodgkin transformation can in many cases be successfully treated with standard Hodgkin regimen, the natural history and optimal treatment for CLL with Hodgkin-like cells have been unknown. This analysis helps understand the biologic difference between these two clinicopathologic entities to understand how to better treat patients,” she noted. Going forward, “it would be extremely helpful to see these data validated by other centers to be sure that these results are reproducible,” Dr. Woyach added.
The study was supported by the Mayo Clinic, Rochester, Minn., and by the Henry J. Predolin Foundation. Lead author Dr. King disclosed research support to her institution from Bristol-Myers Squibb/Celgene. Dr. Woyach had no financial disclosures relevant to this study, but she has received laboratory research funding from Schrodinger and has consulted for AbbVie, Pharmacyclics, Janssen, AstraZeneca, Genentech, Beigene, Loxo, and Newave.
This article was updated 3/11/22.
Patients who have a rare subtype of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with isolated Hodgkin/Reed–Sternberg-like cells (CLL-HRS) may benefit from Hodgkin-directed therapy, based on data from 46 individuals.
Those patients who progress to classic Hodgkin lymphoma (CHL) from CLL/SLL are generally diagnosed based on straightforward pathology and treated with HRS cells in the same way as patients with de novo CHL, wrote lead author Dr. Rebecca L. King, a pathologist at the Mayo Clinic in Rochester, Minn.
Given the rarity of CLL-HRS, data on patient management are limited, they noted.
In a retrospective study published in Blood Cancer Journal, researchers reviewed outcome data from 15 adults with CLL-HRS and 31 adults with CLL/SLL who had overtly transformed to CLL-HL. The median age of the participants at the time of CLL-HL or CLL-HRS transformation diagnosis was 72 years; 71% and 87% of the CLL-HL and CLL-HRS patients, respectively, were male.
The median times from CLL to CLL-HL transformation and from CLL to CLL-HRS transformation were 6.6 years and 4.9 years, respectively; the difference was not statistically significant. The phenotypic features of Reed-Sternberg cells and Epstein-Barr virus status were similar in both patient groups. Two patients had biopsies in which both CLL-HRS and CLL-HL were present in the same tissue at initial diagnosis; they were included in the CLL-HL group for clinical analysis and in both groups for pathology analysis.
The median overall survival of CLL-HRS patients was 17.5 months, compared with 33.5 months for CLL-HL patients (P = .24), a nonsignificant difference. However, patients with CLL-HRS who received Hodgkin-directed therapy had a significantly longer median overall survival, compared with those who received CLL-directed therapy (57 months vs. 8.4 months, P = .02).
CLL-directed therapy included rituximab with or without corticosteroids, chemoimmunotherapy, or acalabrutinib; HL-directed therapy included doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine–based treatment; radiotherapy; or BCVPP (carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone).
Histopathology findings showed that CLL-HL patients had a background of mixed inflammation that was distinct from findings in CLL/SLL. CLL-HRS patients had a minimal inflammatory background, compared with CLL-HL cases, but researchers identified rosetting of T cells around the HRS cells in 56% of these patients.
“Our findings suggest that, clinically and pathologically, these patients show a spectrum of findings, and these two entities likely exist on a biologic continuum. Furthermore, our findings suggest that CLL-HRS patients managed with Hodgkin-directed therapy, rather than CLL-directed therapy, may have superior outcomes,” the researchers wrote.
The study findings were limited by several factors, including the retrospective design and the use of data from a single center. Therefore, the results should be validated in other cohorts, the researchers noted. In addition, the study participants were diagnosed over three decades, and management of the condition has significantly improved.
However, the results were strengthened by a review of data by three pathologists who were blinded to the clinical outcomes, they said.
“These findings have important implications for a scenario in which clinical guidelines are lacking and suggest that hematologists treating patients with CLL-HRS should consider HL-directed therapy,” the researchers concluded.
In an interview, Jennifer A. Woyach, MD, a hematologist at Ohio State University, Columbus, commented on the study findings: “Hodgkin transformation and CLL with Hodgkin-like cells likely represent a biologic continuum, and care should be taken to obtain adequate biopsies, so that the diagnosis of Hodgkin transformation can be made when appropriate.”
“Interestingly, the authors noted a trend toward improved survival when CLL with Hodgkin-like cells was treated with standard Hodgkin regimens,” said Dr. Woyach. “With the small patient numbers, this certainly cannot be a general recommendation, but should be considered by treating physicians on a case-by-case basis.”
“While we know that patients with Hodgkin transformation can in many cases be successfully treated with standard Hodgkin regimen, the natural history and optimal treatment for CLL with Hodgkin-like cells have been unknown. This analysis helps understand the biologic difference between these two clinicopathologic entities to understand how to better treat patients,” she noted. Going forward, “it would be extremely helpful to see these data validated by other centers to be sure that these results are reproducible,” Dr. Woyach added.
The study was supported by the Mayo Clinic, Rochester, Minn., and by the Henry J. Predolin Foundation. Lead author Dr. King disclosed research support to her institution from Bristol-Myers Squibb/Celgene. Dr. Woyach had no financial disclosures relevant to this study, but she has received laboratory research funding from Schrodinger and has consulted for AbbVie, Pharmacyclics, Janssen, AstraZeneca, Genentech, Beigene, Loxo, and Newave.
This article was updated 3/11/22.
Patients who have a rare subtype of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with isolated Hodgkin/Reed–Sternberg-like cells (CLL-HRS) may benefit from Hodgkin-directed therapy, based on data from 46 individuals.
Those patients who progress to classic Hodgkin lymphoma (CHL) from CLL/SLL are generally diagnosed based on straightforward pathology and treated with HRS cells in the same way as patients with de novo CHL, wrote lead author Dr. Rebecca L. King, a pathologist at the Mayo Clinic in Rochester, Minn.
Given the rarity of CLL-HRS, data on patient management are limited, they noted.
In a retrospective study published in Blood Cancer Journal, researchers reviewed outcome data from 15 adults with CLL-HRS and 31 adults with CLL/SLL who had overtly transformed to CLL-HL. The median age of the participants at the time of CLL-HL or CLL-HRS transformation diagnosis was 72 years; 71% and 87% of the CLL-HL and CLL-HRS patients, respectively, were male.
The median times from CLL to CLL-HL transformation and from CLL to CLL-HRS transformation were 6.6 years and 4.9 years, respectively; the difference was not statistically significant. The phenotypic features of Reed-Sternberg cells and Epstein-Barr virus status were similar in both patient groups. Two patients had biopsies in which both CLL-HRS and CLL-HL were present in the same tissue at initial diagnosis; they were included in the CLL-HL group for clinical analysis and in both groups for pathology analysis.
The median overall survival of CLL-HRS patients was 17.5 months, compared with 33.5 months for CLL-HL patients (P = .24), a nonsignificant difference. However, patients with CLL-HRS who received Hodgkin-directed therapy had a significantly longer median overall survival, compared with those who received CLL-directed therapy (57 months vs. 8.4 months, P = .02).
CLL-directed therapy included rituximab with or without corticosteroids, chemoimmunotherapy, or acalabrutinib; HL-directed therapy included doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine–based treatment; radiotherapy; or BCVPP (carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone).
Histopathology findings showed that CLL-HL patients had a background of mixed inflammation that was distinct from findings in CLL/SLL. CLL-HRS patients had a minimal inflammatory background, compared with CLL-HL cases, but researchers identified rosetting of T cells around the HRS cells in 56% of these patients.
“Our findings suggest that, clinically and pathologically, these patients show a spectrum of findings, and these two entities likely exist on a biologic continuum. Furthermore, our findings suggest that CLL-HRS patients managed with Hodgkin-directed therapy, rather than CLL-directed therapy, may have superior outcomes,” the researchers wrote.
The study findings were limited by several factors, including the retrospective design and the use of data from a single center. Therefore, the results should be validated in other cohorts, the researchers noted. In addition, the study participants were diagnosed over three decades, and management of the condition has significantly improved.
However, the results were strengthened by a review of data by three pathologists who were blinded to the clinical outcomes, they said.
“These findings have important implications for a scenario in which clinical guidelines are lacking and suggest that hematologists treating patients with CLL-HRS should consider HL-directed therapy,” the researchers concluded.
In an interview, Jennifer A. Woyach, MD, a hematologist at Ohio State University, Columbus, commented on the study findings: “Hodgkin transformation and CLL with Hodgkin-like cells likely represent a biologic continuum, and care should be taken to obtain adequate biopsies, so that the diagnosis of Hodgkin transformation can be made when appropriate.”
“Interestingly, the authors noted a trend toward improved survival when CLL with Hodgkin-like cells was treated with standard Hodgkin regimens,” said Dr. Woyach. “With the small patient numbers, this certainly cannot be a general recommendation, but should be considered by treating physicians on a case-by-case basis.”
“While we know that patients with Hodgkin transformation can in many cases be successfully treated with standard Hodgkin regimen, the natural history and optimal treatment for CLL with Hodgkin-like cells have been unknown. This analysis helps understand the biologic difference between these two clinicopathologic entities to understand how to better treat patients,” she noted. Going forward, “it would be extremely helpful to see these data validated by other centers to be sure that these results are reproducible,” Dr. Woyach added.
The study was supported by the Mayo Clinic, Rochester, Minn., and by the Henry J. Predolin Foundation. Lead author Dr. King disclosed research support to her institution from Bristol-Myers Squibb/Celgene. Dr. Woyach had no financial disclosures relevant to this study, but she has received laboratory research funding from Schrodinger and has consulted for AbbVie, Pharmacyclics, Janssen, AstraZeneca, Genentech, Beigene, Loxo, and Newave.
This article was updated 3/11/22.
FROM BLOOD CANCER JOURNAL
9/11 first responders show mutations linked to blood cancers
. These results add to concerns about the long-term health effects of that exposure and further underscore a need for screening of those exposed.
“These data demonstrate that environmental exposure to the WTC disaster site is associated with a higher burden of clonal hematopoiesis, exceeding that expected in normal aging, and establish a rationale for mutational testing of the larger WTC-exposed population,” report the authors in the study, published March 7 in Nature Medicine.
The findings come from a study of blood samples from WTC first responders, including 429 firefighters and 52 emergency medical service workers, collected between December 2013 and October 2015.
For comparisons, the authors collected blood samples from 255 firefighters from in and around Nashville, Tenn., none of whom had been exposed to the 9/11 disaster.
Genetic analysis of the samples showed that 10% of those in the WTC-exposed cohort (n = 48) had unique somatic mutations considered to likely be pathogenic, and six of those individuals carried one or more of the mutations.
After a multivariate adjustment controlling for age, sex and race/ethnicity, those among the WTC-exposed first responders had a significantly increased odds of clonal hematopoiesis versus nonexposed workers (odds ratio [OR] = 3.14; P = .0006).
The higher risk was further observed in a comparison limited only to the WTC-exposed firefighters versus nonexposed firefighters (OR = 2.93; P = .0014) after the multivariate adjustment. The greater association between WTC exposure and clonal hematopoiesis remained after the researchers controlled for smoking as well as other risk factors among the WTC-exposed group overall (OR = 3.05; P = .0015) and the firefighters-only comparison (OR = 2.78; P = .004).
A history of smoking was not significantly associated with an increased risk of clonal hematopoiesis in either model.
As a risk factor for hematologic malignancy, cardiovascular events, and mortality, “clonal hematopoiesis is a concerning acquired risk not only for diseases that are already associated with WTC exposure but also as the population ages, this may exacerbate their risk profile,” Dr. Anna Nolan, coauthor of the study, and professor of medicine and environmental medicine in the division of pulmonary and critical care, New York University, said in an interview.
The most common gene mutations observed in the WTC-exposed group were those associated with myeloid malignancies, such as chronic myeloid leukemia; however, blood counts in the exposed group showed no association between exposure and mutations linked to cytopenias.
A further analysis on mice, investigating how WTC particulate matter uniquely affects DNA, surprisingly showed that just one exposure to the material was associated with clonal hematopoietic changes.
“Exposure to particulates, even at a single time point, can yield clonal mutations that may be risk for multisystem end-organ changes,” Dr. Nolan said.
While the serious health effects of WTC exposure on humans, have been extensively documented, including a study published in February showing increases in skin, prostate and thyroid cancers, clonal hematopoiesis suggests further heightened risks as the exposed population grows older, Dr. Nolan noted.
“[Clonal hematopoiesis] is a concerning acquired risk not only for diseases that are already associated with WTC exposure, but also, as the population ages, this may exacerbate their risk profile,” she said.
Due to the risk, “clinicians should be aware that WTC-exposed first responders have had a significant exposure and that they are at risk for developing several conditions.”
Commenting on this study, William K. Oh, MD, whose team at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, has reported in a previous study on the increased risk of prostate cancer among WTC first responders, noted that more time may be necessary to better understand the full effects of the increases in clonal hematopoiesis.
“Though these findings are of concern, there were still no differences in the cohorts in actual hematologic cancers or even cytopenias, suggesting that more time and additional DNA damaging events were needed to transform the clonal hematopoiesis findings to clinically relevant diseases,” Dr. Oh, clinical professor of medicine, said in an interview.
Nevertheless, “if a patient is found on testing to have clonal hematopoiesis, they should be screened more closely for blood disorders and cardiovascular issues than they might otherwise be, though this remains an area of active investigation,” Dr. Oh said.
Dr. Nolan had no disclosures to report. Dr. Oh is the chief medical science officer at Sema4, a genomic testing and data company.
. These results add to concerns about the long-term health effects of that exposure and further underscore a need for screening of those exposed.
“These data demonstrate that environmental exposure to the WTC disaster site is associated with a higher burden of clonal hematopoiesis, exceeding that expected in normal aging, and establish a rationale for mutational testing of the larger WTC-exposed population,” report the authors in the study, published March 7 in Nature Medicine.
The findings come from a study of blood samples from WTC first responders, including 429 firefighters and 52 emergency medical service workers, collected between December 2013 and October 2015.
For comparisons, the authors collected blood samples from 255 firefighters from in and around Nashville, Tenn., none of whom had been exposed to the 9/11 disaster.
Genetic analysis of the samples showed that 10% of those in the WTC-exposed cohort (n = 48) had unique somatic mutations considered to likely be pathogenic, and six of those individuals carried one or more of the mutations.
After a multivariate adjustment controlling for age, sex and race/ethnicity, those among the WTC-exposed first responders had a significantly increased odds of clonal hematopoiesis versus nonexposed workers (odds ratio [OR] = 3.14; P = .0006).
The higher risk was further observed in a comparison limited only to the WTC-exposed firefighters versus nonexposed firefighters (OR = 2.93; P = .0014) after the multivariate adjustment. The greater association between WTC exposure and clonal hematopoiesis remained after the researchers controlled for smoking as well as other risk factors among the WTC-exposed group overall (OR = 3.05; P = .0015) and the firefighters-only comparison (OR = 2.78; P = .004).
A history of smoking was not significantly associated with an increased risk of clonal hematopoiesis in either model.
As a risk factor for hematologic malignancy, cardiovascular events, and mortality, “clonal hematopoiesis is a concerning acquired risk not only for diseases that are already associated with WTC exposure but also as the population ages, this may exacerbate their risk profile,” Dr. Anna Nolan, coauthor of the study, and professor of medicine and environmental medicine in the division of pulmonary and critical care, New York University, said in an interview.
The most common gene mutations observed in the WTC-exposed group were those associated with myeloid malignancies, such as chronic myeloid leukemia; however, blood counts in the exposed group showed no association between exposure and mutations linked to cytopenias.
A further analysis on mice, investigating how WTC particulate matter uniquely affects DNA, surprisingly showed that just one exposure to the material was associated with clonal hematopoietic changes.
“Exposure to particulates, even at a single time point, can yield clonal mutations that may be risk for multisystem end-organ changes,” Dr. Nolan said.
While the serious health effects of WTC exposure on humans, have been extensively documented, including a study published in February showing increases in skin, prostate and thyroid cancers, clonal hematopoiesis suggests further heightened risks as the exposed population grows older, Dr. Nolan noted.
“[Clonal hematopoiesis] is a concerning acquired risk not only for diseases that are already associated with WTC exposure, but also, as the population ages, this may exacerbate their risk profile,” she said.
Due to the risk, “clinicians should be aware that WTC-exposed first responders have had a significant exposure and that they are at risk for developing several conditions.”
Commenting on this study, William K. Oh, MD, whose team at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, has reported in a previous study on the increased risk of prostate cancer among WTC first responders, noted that more time may be necessary to better understand the full effects of the increases in clonal hematopoiesis.
“Though these findings are of concern, there were still no differences in the cohorts in actual hematologic cancers or even cytopenias, suggesting that more time and additional DNA damaging events were needed to transform the clonal hematopoiesis findings to clinically relevant diseases,” Dr. Oh, clinical professor of medicine, said in an interview.
Nevertheless, “if a patient is found on testing to have clonal hematopoiesis, they should be screened more closely for blood disorders and cardiovascular issues than they might otherwise be, though this remains an area of active investigation,” Dr. Oh said.
Dr. Nolan had no disclosures to report. Dr. Oh is the chief medical science officer at Sema4, a genomic testing and data company.
. These results add to concerns about the long-term health effects of that exposure and further underscore a need for screening of those exposed.
“These data demonstrate that environmental exposure to the WTC disaster site is associated with a higher burden of clonal hematopoiesis, exceeding that expected in normal aging, and establish a rationale for mutational testing of the larger WTC-exposed population,” report the authors in the study, published March 7 in Nature Medicine.
The findings come from a study of blood samples from WTC first responders, including 429 firefighters and 52 emergency medical service workers, collected between December 2013 and October 2015.
For comparisons, the authors collected blood samples from 255 firefighters from in and around Nashville, Tenn., none of whom had been exposed to the 9/11 disaster.
Genetic analysis of the samples showed that 10% of those in the WTC-exposed cohort (n = 48) had unique somatic mutations considered to likely be pathogenic, and six of those individuals carried one or more of the mutations.
After a multivariate adjustment controlling for age, sex and race/ethnicity, those among the WTC-exposed first responders had a significantly increased odds of clonal hematopoiesis versus nonexposed workers (odds ratio [OR] = 3.14; P = .0006).
The higher risk was further observed in a comparison limited only to the WTC-exposed firefighters versus nonexposed firefighters (OR = 2.93; P = .0014) after the multivariate adjustment. The greater association between WTC exposure and clonal hematopoiesis remained after the researchers controlled for smoking as well as other risk factors among the WTC-exposed group overall (OR = 3.05; P = .0015) and the firefighters-only comparison (OR = 2.78; P = .004).
A history of smoking was not significantly associated with an increased risk of clonal hematopoiesis in either model.
As a risk factor for hematologic malignancy, cardiovascular events, and mortality, “clonal hematopoiesis is a concerning acquired risk not only for diseases that are already associated with WTC exposure but also as the population ages, this may exacerbate their risk profile,” Dr. Anna Nolan, coauthor of the study, and professor of medicine and environmental medicine in the division of pulmonary and critical care, New York University, said in an interview.
The most common gene mutations observed in the WTC-exposed group were those associated with myeloid malignancies, such as chronic myeloid leukemia; however, blood counts in the exposed group showed no association between exposure and mutations linked to cytopenias.
A further analysis on mice, investigating how WTC particulate matter uniquely affects DNA, surprisingly showed that just one exposure to the material was associated with clonal hematopoietic changes.
“Exposure to particulates, even at a single time point, can yield clonal mutations that may be risk for multisystem end-organ changes,” Dr. Nolan said.
While the serious health effects of WTC exposure on humans, have been extensively documented, including a study published in February showing increases in skin, prostate and thyroid cancers, clonal hematopoiesis suggests further heightened risks as the exposed population grows older, Dr. Nolan noted.
“[Clonal hematopoiesis] is a concerning acquired risk not only for diseases that are already associated with WTC exposure, but also, as the population ages, this may exacerbate their risk profile,” she said.
Due to the risk, “clinicians should be aware that WTC-exposed first responders have had a significant exposure and that they are at risk for developing several conditions.”
Commenting on this study, William K. Oh, MD, whose team at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, has reported in a previous study on the increased risk of prostate cancer among WTC first responders, noted that more time may be necessary to better understand the full effects of the increases in clonal hematopoiesis.
“Though these findings are of concern, there were still no differences in the cohorts in actual hematologic cancers or even cytopenias, suggesting that more time and additional DNA damaging events were needed to transform the clonal hematopoiesis findings to clinically relevant diseases,” Dr. Oh, clinical professor of medicine, said in an interview.
Nevertheless, “if a patient is found on testing to have clonal hematopoiesis, they should be screened more closely for blood disorders and cardiovascular issues than they might otherwise be, though this remains an area of active investigation,” Dr. Oh said.
Dr. Nolan had no disclosures to report. Dr. Oh is the chief medical science officer at Sema4, a genomic testing and data company.
FROM NATURE MEDICINE
Global data suggest rising CLL incidence since 1990
Either way, “to our best knowledge, this study is the first study to provide a comprehensive description of the epidemiology and global burden of CLL worldwide,” the authors reported in BioMedical Engineering Online.
The findings are an evaluation of data from the 2019 Global Burden of Disease study, which includes epidemiological data on 369 diseases in 204 nations and territories around the world.
According to the analysis, the age-standardized incidence rate of CLL rose globally over the last 3 decades, from 0.76 per 100,000 persons in 1990 to 1.34 per 100,000 in 2019, for an estimated annual percentage change of 1.86%.
While increases were observed across all economic levels, the highest increases were observed in regions with the highest social determinant index. Notably, the fastest rise was observed in middle-income regions.
“What cannot be ignored is the rapid growth of the disease burden in middle [social determinant index] regions, which potentially indicated an underestimated incidence and mortality in underdeveloped countries,” write the authors, led by senior author Huafeng Wang, MD, of the department of hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
The highest annual age-standardized incidence rates in 2019 occurred in western Europe, high-income areas of North America and central Europe, while the fastest increase in the incidence of CLL occurred in east Asia, central Europe, and Andean Latin America, according to the study.
Mortality rates
The age-standardized death rate from CLL also increased globally, from 0.40 per 100,000 persons in 1990 to 0.58 per 100,000 in 2019, for an estimated annual percentage change of 1.17.
The increases in death rates were observed across all income regions over the study period, with the highest age-standardized death rate in 2019, consistent with incidence rates, occurring in the highest-income regions, specifically in central Europe, western Europe, and high-income North America.
The geographic trends were similar in terms of disability-adjusted life-years, which increased globally from 9.20 per 100,000 persons in 1990 to 12.26 per 100,000 in 2019, for an estimated annual percentage change of 0.92%.
The authors noted that the geographic variation of CLL is consistent with research suggesting that White ancestry is a risk factor for this leukemia. And while the incidence of CLL is generally low in the 22 nations of the Arab League, the burden of disease is high in Israel.
Age and gender
The study shows that, during the past 30 years in general, CLL was more common among males, with some regional differences. For instance, in contrast to global trends, females in low-income regions accounted for the majority of incidence and mortality.
The majority of CLL cases occurred in people over the age of 50, which is consistent with known patterns of CLL occurring in older patients. Of note, the majority of cases between the ages of 50 and 69 were in low-income regions, while more than half of the incidence cases in higher-income regions were among those over the age of 70.
Risk factors
Key risk factors that may to be linked to CLL-related mortality and disability include high body mass index, occupational exposure to benzene and formaldehyde, and smoking, which was the strongest risk factor, the authors reported.
Obesity has previously been linked with an increased risk of lymphohematopoietic cancers in general and with poorer responses to treatment and reduced progression-free survival in CLL, in particular.
While the database otherwise provided only limited insights into potential CLL risk factors, “among the factors [the database] provided, the risk of benzene and formaldehyde exposure should be paid attention to,” Dr. Wang said in an interview.
“Different from other risk factors, emerging evidence has clearly pointed out the close relationship between benzene and formaldehyde exposure and hematological malignancies,” he explained. “With globalization, a large number of factories moved to less developed regions. The problem of occupational toxic exposure needs to be addressed.”
In general, the trends in the current study are consistent with previous research showing that, while there was a significant global decrease in leukemia incidence between 1990 and 2017, the incidence rates of CLL as well as acute myeloid leukemia (AML) significantly increased in most countries during that period.
“The age-standardized incidence rate of AML has steadily increased over the past 30 years, but not as rapidly as CLL,” Dr. Wang said.
He added that an encouraging sign is the “significant decline” in the age-standardized rate of chronic myeloid leukemia seen with the advent of tyrosine kinase inhibitors (TKIs).
“Perhaps for CLL, the emergence of epoch-making therapies like TKIs will also contribute to the reduction of disease burden [with that disease],” he said.
Surveillance bias?
The authors note a key caveat that the lower rates observed in low-income regions could be related to underreporting and lower screening of cancers in those regions. However, commenting on the study, Robert Peter Gale, MD, PhD, suggested that, conversely, the trends may represent a surveillance bias, reflecting an increased detection of CLL.
In fact, “it is most unlikely the incidence of CLL is really increasing,” Dr. Gale, visiting professor of hematology at the Hematology Research Centre, department of immunology and inflammation, Imperial College London, said in an interview.
“More than one-half of people with CLL have no signs or symptoms, and the diagnosis is made when they have a blood test done for unrelated reasons,” such as in the process of qualifying for life or medical insurance or for a new job, he explained. “The more testing you do, the more cases you will detect.”
Dr. Gale pointed out that research his team has conducted in China also showed an increasing incidence of CLL. However, “on closer study, we found about two-thirds of cases were incidental, namely cases detected under circumstances [such as blood testing for a job].”
Shen-Miao Yang, MD, first author of that study, agreed and noted that improved treatment with drugs such as Bruton kinase inhibitors also can have the effect of increasing incidence – by extending lives.
“More patients are diagnosed, [and] receive the new agent, and their longer survival contributes to the increased burden of CLL,” Dr. Yang of People’s Hospital of Peking University, Peking University Institute of Hematology, Beijing, said in an interview.
Furthermore, “advanced techniques such as flow cytometry and fluorescence in situ hybridization are routinely used for the diagnosis and prognosis of CLL patients – that also increases the CLL burden.”
Dr. Yang had no disclosures to report. Dr. Gale disclosed that he is a consultant to BeiGene, Fusion Pharma, La Jolla NanoMedical, MingSight Pharmaceuticals, CStone Pharmaceuticals, NexImmune, and Prolacta Bioscience; an adviser to Antengene Biotech; medical director of FFF Enterprises; a partner of AZCA; member of the board of directors of the Russian Foundation for Cancer Research Support; and on the scientific advisory board of StemRad.
Either way, “to our best knowledge, this study is the first study to provide a comprehensive description of the epidemiology and global burden of CLL worldwide,” the authors reported in BioMedical Engineering Online.
The findings are an evaluation of data from the 2019 Global Burden of Disease study, which includes epidemiological data on 369 diseases in 204 nations and territories around the world.
According to the analysis, the age-standardized incidence rate of CLL rose globally over the last 3 decades, from 0.76 per 100,000 persons in 1990 to 1.34 per 100,000 in 2019, for an estimated annual percentage change of 1.86%.
While increases were observed across all economic levels, the highest increases were observed in regions with the highest social determinant index. Notably, the fastest rise was observed in middle-income regions.
“What cannot be ignored is the rapid growth of the disease burden in middle [social determinant index] regions, which potentially indicated an underestimated incidence and mortality in underdeveloped countries,” write the authors, led by senior author Huafeng Wang, MD, of the department of hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
The highest annual age-standardized incidence rates in 2019 occurred in western Europe, high-income areas of North America and central Europe, while the fastest increase in the incidence of CLL occurred in east Asia, central Europe, and Andean Latin America, according to the study.
Mortality rates
The age-standardized death rate from CLL also increased globally, from 0.40 per 100,000 persons in 1990 to 0.58 per 100,000 in 2019, for an estimated annual percentage change of 1.17.
The increases in death rates were observed across all income regions over the study period, with the highest age-standardized death rate in 2019, consistent with incidence rates, occurring in the highest-income regions, specifically in central Europe, western Europe, and high-income North America.
The geographic trends were similar in terms of disability-adjusted life-years, which increased globally from 9.20 per 100,000 persons in 1990 to 12.26 per 100,000 in 2019, for an estimated annual percentage change of 0.92%.
The authors noted that the geographic variation of CLL is consistent with research suggesting that White ancestry is a risk factor for this leukemia. And while the incidence of CLL is generally low in the 22 nations of the Arab League, the burden of disease is high in Israel.
Age and gender
The study shows that, during the past 30 years in general, CLL was more common among males, with some regional differences. For instance, in contrast to global trends, females in low-income regions accounted for the majority of incidence and mortality.
The majority of CLL cases occurred in people over the age of 50, which is consistent with known patterns of CLL occurring in older patients. Of note, the majority of cases between the ages of 50 and 69 were in low-income regions, while more than half of the incidence cases in higher-income regions were among those over the age of 70.
Risk factors
Key risk factors that may to be linked to CLL-related mortality and disability include high body mass index, occupational exposure to benzene and formaldehyde, and smoking, which was the strongest risk factor, the authors reported.
Obesity has previously been linked with an increased risk of lymphohematopoietic cancers in general and with poorer responses to treatment and reduced progression-free survival in CLL, in particular.
While the database otherwise provided only limited insights into potential CLL risk factors, “among the factors [the database] provided, the risk of benzene and formaldehyde exposure should be paid attention to,” Dr. Wang said in an interview.
“Different from other risk factors, emerging evidence has clearly pointed out the close relationship between benzene and formaldehyde exposure and hematological malignancies,” he explained. “With globalization, a large number of factories moved to less developed regions. The problem of occupational toxic exposure needs to be addressed.”
In general, the trends in the current study are consistent with previous research showing that, while there was a significant global decrease in leukemia incidence between 1990 and 2017, the incidence rates of CLL as well as acute myeloid leukemia (AML) significantly increased in most countries during that period.
“The age-standardized incidence rate of AML has steadily increased over the past 30 years, but not as rapidly as CLL,” Dr. Wang said.
He added that an encouraging sign is the “significant decline” in the age-standardized rate of chronic myeloid leukemia seen with the advent of tyrosine kinase inhibitors (TKIs).
“Perhaps for CLL, the emergence of epoch-making therapies like TKIs will also contribute to the reduction of disease burden [with that disease],” he said.
Surveillance bias?
The authors note a key caveat that the lower rates observed in low-income regions could be related to underreporting and lower screening of cancers in those regions. However, commenting on the study, Robert Peter Gale, MD, PhD, suggested that, conversely, the trends may represent a surveillance bias, reflecting an increased detection of CLL.
In fact, “it is most unlikely the incidence of CLL is really increasing,” Dr. Gale, visiting professor of hematology at the Hematology Research Centre, department of immunology and inflammation, Imperial College London, said in an interview.
“More than one-half of people with CLL have no signs or symptoms, and the diagnosis is made when they have a blood test done for unrelated reasons,” such as in the process of qualifying for life or medical insurance or for a new job, he explained. “The more testing you do, the more cases you will detect.”
Dr. Gale pointed out that research his team has conducted in China also showed an increasing incidence of CLL. However, “on closer study, we found about two-thirds of cases were incidental, namely cases detected under circumstances [such as blood testing for a job].”
Shen-Miao Yang, MD, first author of that study, agreed and noted that improved treatment with drugs such as Bruton kinase inhibitors also can have the effect of increasing incidence – by extending lives.
“More patients are diagnosed, [and] receive the new agent, and their longer survival contributes to the increased burden of CLL,” Dr. Yang of People’s Hospital of Peking University, Peking University Institute of Hematology, Beijing, said in an interview.
Furthermore, “advanced techniques such as flow cytometry and fluorescence in situ hybridization are routinely used for the diagnosis and prognosis of CLL patients – that also increases the CLL burden.”
Dr. Yang had no disclosures to report. Dr. Gale disclosed that he is a consultant to BeiGene, Fusion Pharma, La Jolla NanoMedical, MingSight Pharmaceuticals, CStone Pharmaceuticals, NexImmune, and Prolacta Bioscience; an adviser to Antengene Biotech; medical director of FFF Enterprises; a partner of AZCA; member of the board of directors of the Russian Foundation for Cancer Research Support; and on the scientific advisory board of StemRad.
Either way, “to our best knowledge, this study is the first study to provide a comprehensive description of the epidemiology and global burden of CLL worldwide,” the authors reported in BioMedical Engineering Online.
The findings are an evaluation of data from the 2019 Global Burden of Disease study, which includes epidemiological data on 369 diseases in 204 nations and territories around the world.
According to the analysis, the age-standardized incidence rate of CLL rose globally over the last 3 decades, from 0.76 per 100,000 persons in 1990 to 1.34 per 100,000 in 2019, for an estimated annual percentage change of 1.86%.
While increases were observed across all economic levels, the highest increases were observed in regions with the highest social determinant index. Notably, the fastest rise was observed in middle-income regions.
“What cannot be ignored is the rapid growth of the disease burden in middle [social determinant index] regions, which potentially indicated an underestimated incidence and mortality in underdeveloped countries,” write the authors, led by senior author Huafeng Wang, MD, of the department of hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
The highest annual age-standardized incidence rates in 2019 occurred in western Europe, high-income areas of North America and central Europe, while the fastest increase in the incidence of CLL occurred in east Asia, central Europe, and Andean Latin America, according to the study.
Mortality rates
The age-standardized death rate from CLL also increased globally, from 0.40 per 100,000 persons in 1990 to 0.58 per 100,000 in 2019, for an estimated annual percentage change of 1.17.
The increases in death rates were observed across all income regions over the study period, with the highest age-standardized death rate in 2019, consistent with incidence rates, occurring in the highest-income regions, specifically in central Europe, western Europe, and high-income North America.
The geographic trends were similar in terms of disability-adjusted life-years, which increased globally from 9.20 per 100,000 persons in 1990 to 12.26 per 100,000 in 2019, for an estimated annual percentage change of 0.92%.
The authors noted that the geographic variation of CLL is consistent with research suggesting that White ancestry is a risk factor for this leukemia. And while the incidence of CLL is generally low in the 22 nations of the Arab League, the burden of disease is high in Israel.
Age and gender
The study shows that, during the past 30 years in general, CLL was more common among males, with some regional differences. For instance, in contrast to global trends, females in low-income regions accounted for the majority of incidence and mortality.
The majority of CLL cases occurred in people over the age of 50, which is consistent with known patterns of CLL occurring in older patients. Of note, the majority of cases between the ages of 50 and 69 were in low-income regions, while more than half of the incidence cases in higher-income regions were among those over the age of 70.
Risk factors
Key risk factors that may to be linked to CLL-related mortality and disability include high body mass index, occupational exposure to benzene and formaldehyde, and smoking, which was the strongest risk factor, the authors reported.
Obesity has previously been linked with an increased risk of lymphohematopoietic cancers in general and with poorer responses to treatment and reduced progression-free survival in CLL, in particular.
While the database otherwise provided only limited insights into potential CLL risk factors, “among the factors [the database] provided, the risk of benzene and formaldehyde exposure should be paid attention to,” Dr. Wang said in an interview.
“Different from other risk factors, emerging evidence has clearly pointed out the close relationship between benzene and formaldehyde exposure and hematological malignancies,” he explained. “With globalization, a large number of factories moved to less developed regions. The problem of occupational toxic exposure needs to be addressed.”
In general, the trends in the current study are consistent with previous research showing that, while there was a significant global decrease in leukemia incidence between 1990 and 2017, the incidence rates of CLL as well as acute myeloid leukemia (AML) significantly increased in most countries during that period.
“The age-standardized incidence rate of AML has steadily increased over the past 30 years, but not as rapidly as CLL,” Dr. Wang said.
He added that an encouraging sign is the “significant decline” in the age-standardized rate of chronic myeloid leukemia seen with the advent of tyrosine kinase inhibitors (TKIs).
“Perhaps for CLL, the emergence of epoch-making therapies like TKIs will also contribute to the reduction of disease burden [with that disease],” he said.
Surveillance bias?
The authors note a key caveat that the lower rates observed in low-income regions could be related to underreporting and lower screening of cancers in those regions. However, commenting on the study, Robert Peter Gale, MD, PhD, suggested that, conversely, the trends may represent a surveillance bias, reflecting an increased detection of CLL.
In fact, “it is most unlikely the incidence of CLL is really increasing,” Dr. Gale, visiting professor of hematology at the Hematology Research Centre, department of immunology and inflammation, Imperial College London, said in an interview.
“More than one-half of people with CLL have no signs or symptoms, and the diagnosis is made when they have a blood test done for unrelated reasons,” such as in the process of qualifying for life or medical insurance or for a new job, he explained. “The more testing you do, the more cases you will detect.”
Dr. Gale pointed out that research his team has conducted in China also showed an increasing incidence of CLL. However, “on closer study, we found about two-thirds of cases were incidental, namely cases detected under circumstances [such as blood testing for a job].”
Shen-Miao Yang, MD, first author of that study, agreed and noted that improved treatment with drugs such as Bruton kinase inhibitors also can have the effect of increasing incidence – by extending lives.
“More patients are diagnosed, [and] receive the new agent, and their longer survival contributes to the increased burden of CLL,” Dr. Yang of People’s Hospital of Peking University, Peking University Institute of Hematology, Beijing, said in an interview.
Furthermore, “advanced techniques such as flow cytometry and fluorescence in situ hybridization are routinely used for the diagnosis and prognosis of CLL patients – that also increases the CLL burden.”
Dr. Yang had no disclosures to report. Dr. Gale disclosed that he is a consultant to BeiGene, Fusion Pharma, La Jolla NanoMedical, MingSight Pharmaceuticals, CStone Pharmaceuticals, NexImmune, and Prolacta Bioscience; an adviser to Antengene Biotech; medical director of FFF Enterprises; a partner of AZCA; member of the board of directors of the Russian Foundation for Cancer Research Support; and on the scientific advisory board of StemRad.
FROM BIOMEDICAL ENGINEERING ONLINE