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Flavopiridol elicits poor response in mantle cell lymphoma, DLBCL
Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.
“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.
The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.
The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).
The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.
Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.
“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.
With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.
The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.
Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.
“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.
The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.
SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.
Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.
“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.
The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.
The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).
The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.
Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.
“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.
With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.
The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.
Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.
“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.
The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.
SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.
Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.
“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.
The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.
The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).
The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.
Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.
“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.
With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.
The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.
Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.
“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.
The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.
SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.
FROM LEUKEMIA & LYMPHOMA
On second thought, lenalidomide does improve DLBCL outcomes
LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.
Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.
“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.
So what’s behind the conflicting findings?
The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.
The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.
In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
ECOG-ACRIN 1412 details
Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.
To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.
The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.
The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.
In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.
The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.
Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.
The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.
After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.
There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.
Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.
R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.
Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.
In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.
“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.
Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.
ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.
SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.
LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.
Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.
“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.
So what’s behind the conflicting findings?
The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.
The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.
In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
ECOG-ACRIN 1412 details
Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.
To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.
The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.
The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.
In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.
The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.
Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.
The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.
After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.
There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.
Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.
R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.
Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.
In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.
“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.
Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.
ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.
SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.
LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.
Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.
“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.
So what’s behind the conflicting findings?
The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.
The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.
In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
ECOG-ACRIN 1412 details
Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.
To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.
The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.
The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.
In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.
The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.
Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.
The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.
After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.
There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.
Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.
R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.
Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.
In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.
“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.
Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.
ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.
SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.
REPORTING FROM 15-ICML
SC daratumumab deemed feasible for every multiple myeloma patient
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
REPORTING FROM ASCO 2019
R2-CHOP doesn’t improve survival in DLBCL
LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.
Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.
The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.
The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.
The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.
In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.
All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.
The efficacy analysis was by intention-to-treat and included 285 patients in each arm.
The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.
Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.
Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.
In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.
The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.
SOURCE: Vitolo U et al. 15-ICML, Abstract 005.
LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.
Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.
The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.
The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.
The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.
In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.
All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.
The efficacy analysis was by intention-to-treat and included 285 patients in each arm.
The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.
Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.
Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.
In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.
The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.
SOURCE: Vitolo U et al. 15-ICML, Abstract 005.
LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.
Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.
The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.
The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.
The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.
In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.
All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.
The efficacy analysis was by intention-to-treat and included 285 patients in each arm.
The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.
Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.
Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.
In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.
The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.
SOURCE: Vitolo U et al. 15-ICML, Abstract 005.
REPORTING FROM 15-ICML
CNS-directed therapy appears more effective for synDLBCL
Controlling CNS disease is “paramount” in treating diffuse large B-cell lymphoma with synchronous CNS and systemic disease (synDLBCL), according to researchers.
In a retrospective study, the CNS was the most common site of relapse in patients with synDLBCL, and patients had better outcomes when they received CNS-directed therapy.
The 2-year progression-free survival rate was 50% in patients who received CNS-intensive therapy and 31% in those who received CNS-conservative therapy. The 2-year overall survival rate was 54% and 44%, respectively.
Dr. Joel C. Wight, of Austin Health in Heidelberg, Australia, and colleagues conducted this study and recounted their findings in the British Journal of Haematology.
The researchers retrospectively analyzed 80 patients with synDLBCL treated at 10 centers in Australia and the United Kingdom. Patients had DLBCL not otherwise specified (n = 67); high-grade B-cell lymphoma, including double-hit lymphoma (n = 12); or T-cell histiocyte-rich DLBCL (n = 1).
At baseline, all patients were treatment-naive, they had a median age of 64 years (range, 18-87 years), and 68% were male. Seventy percent of patients had high-risk disease according to the CNS International Prognostic Index (IPI), and 96% had non-CNS extranodal disease. The median number of extranodal sites outside the CNS was 2 (range, 0 to more than 10).
Patients were divided into those who received CNS-intensive therapy (n = 38) and those given CNS-conservative therapy (n = 42). The CNS-conservative group was significantly older (P less than .001), significantly more likely to have high-risk disease according to the National Comprehensive Cancer Network IPI (P = .009) or CNS IPI (P = .01) and significantly more likely to have leptomeningeal disease only (P less than .001).
Treatment
CNS-intensive therapy was defined as any established multiagent IV chemotherapy regimen with two or more CNS-penetrating drugs and cytarabine, with or without intrathecal chemotherapy and/or radiotherapy.
CNS-conservative therapy was defined as one or fewer IV CNS-penetrating chemotherapy agents in induction, with or without intrathecal chemotherapy and/or radiotherapy.
Systemic induction in the CNS-intensive group consisted of R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with IV methotrexate and cytarabine) in 66% of patients and R-CODOX-M/IVAC (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine) in 24% of patients.
The most common systemic induction regimens in the CNS-conservative group were R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, given to 83% of patients.
CNS-directed IV therapy was given to 100% of the CNS-intensive group and 60% of the CNS-conservative group. This consisted of IV methotrexate plus cytarabine (97%) or MATRix (methotrexate, cytarabine, and thiotepa; 3%) in the CNS-intensive group and high-dose methotrexate in the conservative group.
Intrathecal chemotherapy was given to 97% of the CNS-intensive group and 60% of the CNS-conservative group. CNS-directed radiation was given to 32% and 19%, respectively.
Thirteen patients in the CNS-intensive group and one in the CNS-conservative group underwent autologous transplant as consolidation.
Outcomes
Dose reductions were more frequent in the CNS-conservative group than in the CNS-intensive group, at 48% and 18% (P = .009), as was early cessation of chemotherapy, at 52% and 18% (P = .002). Rates of treatment-related mortality were similar, at 13% in the CNS-intensive group and 12% in the CNS-conservative group.
At the end of induction, the complete response rate was 69% in the CNS-intensive group and 51% in the CNS-conservative group (P = .16). Primary refractory disease was observed in 19% and 38% of patients, respectively (P = .07).
The CNS was the most common site of relapse or progression (n = 28). CNS progression or relapse occurred in 25% of the CNS-intensive group and 49% of the CNS-conservative group (P = .03).
The 2-year progression-free survival rate was 50% for the CNS-intensive group and 31% for the CNS-conservative group (P = .006). The 2-year overall survival rate was 54% and 44%, respectively (P = .037).
When patients were matched for induction outcomes, consolidative transplant did not improve survival.
“The most significant factor affecting survival was the ability to control the CNS disease, which was improved by the addition of IV cytarabine to [high-dose methotrexate],” the researchers wrote.
“Whilst the younger age and more intensive systemic treatment of the CNS-intensive group may have contributed to the improved survival, it is clear that CNS disease control was substantially improved by the addition of cytarabine with lower rates of CNS relapse/progression observed.”
The researchers noted that “adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.”
There was no formal funding for this study, and the researchers did not provide financial disclosures.
SOURCE: Wight JC et al. Br J Haematol. 2019 Jun 24. doi: 10.1111/bjh.16064.
Controlling CNS disease is “paramount” in treating diffuse large B-cell lymphoma with synchronous CNS and systemic disease (synDLBCL), according to researchers.
In a retrospective study, the CNS was the most common site of relapse in patients with synDLBCL, and patients had better outcomes when they received CNS-directed therapy.
The 2-year progression-free survival rate was 50% in patients who received CNS-intensive therapy and 31% in those who received CNS-conservative therapy. The 2-year overall survival rate was 54% and 44%, respectively.
Dr. Joel C. Wight, of Austin Health in Heidelberg, Australia, and colleagues conducted this study and recounted their findings in the British Journal of Haematology.
The researchers retrospectively analyzed 80 patients with synDLBCL treated at 10 centers in Australia and the United Kingdom. Patients had DLBCL not otherwise specified (n = 67); high-grade B-cell lymphoma, including double-hit lymphoma (n = 12); or T-cell histiocyte-rich DLBCL (n = 1).
At baseline, all patients were treatment-naive, they had a median age of 64 years (range, 18-87 years), and 68% were male. Seventy percent of patients had high-risk disease according to the CNS International Prognostic Index (IPI), and 96% had non-CNS extranodal disease. The median number of extranodal sites outside the CNS was 2 (range, 0 to more than 10).
Patients were divided into those who received CNS-intensive therapy (n = 38) and those given CNS-conservative therapy (n = 42). The CNS-conservative group was significantly older (P less than .001), significantly more likely to have high-risk disease according to the National Comprehensive Cancer Network IPI (P = .009) or CNS IPI (P = .01) and significantly more likely to have leptomeningeal disease only (P less than .001).
Treatment
CNS-intensive therapy was defined as any established multiagent IV chemotherapy regimen with two or more CNS-penetrating drugs and cytarabine, with or without intrathecal chemotherapy and/or radiotherapy.
CNS-conservative therapy was defined as one or fewer IV CNS-penetrating chemotherapy agents in induction, with or without intrathecal chemotherapy and/or radiotherapy.
Systemic induction in the CNS-intensive group consisted of R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with IV methotrexate and cytarabine) in 66% of patients and R-CODOX-M/IVAC (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine) in 24% of patients.
The most common systemic induction regimens in the CNS-conservative group were R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, given to 83% of patients.
CNS-directed IV therapy was given to 100% of the CNS-intensive group and 60% of the CNS-conservative group. This consisted of IV methotrexate plus cytarabine (97%) or MATRix (methotrexate, cytarabine, and thiotepa; 3%) in the CNS-intensive group and high-dose methotrexate in the conservative group.
Intrathecal chemotherapy was given to 97% of the CNS-intensive group and 60% of the CNS-conservative group. CNS-directed radiation was given to 32% and 19%, respectively.
Thirteen patients in the CNS-intensive group and one in the CNS-conservative group underwent autologous transplant as consolidation.
Outcomes
Dose reductions were more frequent in the CNS-conservative group than in the CNS-intensive group, at 48% and 18% (P = .009), as was early cessation of chemotherapy, at 52% and 18% (P = .002). Rates of treatment-related mortality were similar, at 13% in the CNS-intensive group and 12% in the CNS-conservative group.
At the end of induction, the complete response rate was 69% in the CNS-intensive group and 51% in the CNS-conservative group (P = .16). Primary refractory disease was observed in 19% and 38% of patients, respectively (P = .07).
The CNS was the most common site of relapse or progression (n = 28). CNS progression or relapse occurred in 25% of the CNS-intensive group and 49% of the CNS-conservative group (P = .03).
The 2-year progression-free survival rate was 50% for the CNS-intensive group and 31% for the CNS-conservative group (P = .006). The 2-year overall survival rate was 54% and 44%, respectively (P = .037).
When patients were matched for induction outcomes, consolidative transplant did not improve survival.
“The most significant factor affecting survival was the ability to control the CNS disease, which was improved by the addition of IV cytarabine to [high-dose methotrexate],” the researchers wrote.
“Whilst the younger age and more intensive systemic treatment of the CNS-intensive group may have contributed to the improved survival, it is clear that CNS disease control was substantially improved by the addition of cytarabine with lower rates of CNS relapse/progression observed.”
The researchers noted that “adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.”
There was no formal funding for this study, and the researchers did not provide financial disclosures.
SOURCE: Wight JC et al. Br J Haematol. 2019 Jun 24. doi: 10.1111/bjh.16064.
Controlling CNS disease is “paramount” in treating diffuse large B-cell lymphoma with synchronous CNS and systemic disease (synDLBCL), according to researchers.
In a retrospective study, the CNS was the most common site of relapse in patients with synDLBCL, and patients had better outcomes when they received CNS-directed therapy.
The 2-year progression-free survival rate was 50% in patients who received CNS-intensive therapy and 31% in those who received CNS-conservative therapy. The 2-year overall survival rate was 54% and 44%, respectively.
Dr. Joel C. Wight, of Austin Health in Heidelberg, Australia, and colleagues conducted this study and recounted their findings in the British Journal of Haematology.
The researchers retrospectively analyzed 80 patients with synDLBCL treated at 10 centers in Australia and the United Kingdom. Patients had DLBCL not otherwise specified (n = 67); high-grade B-cell lymphoma, including double-hit lymphoma (n = 12); or T-cell histiocyte-rich DLBCL (n = 1).
At baseline, all patients were treatment-naive, they had a median age of 64 years (range, 18-87 years), and 68% were male. Seventy percent of patients had high-risk disease according to the CNS International Prognostic Index (IPI), and 96% had non-CNS extranodal disease. The median number of extranodal sites outside the CNS was 2 (range, 0 to more than 10).
Patients were divided into those who received CNS-intensive therapy (n = 38) and those given CNS-conservative therapy (n = 42). The CNS-conservative group was significantly older (P less than .001), significantly more likely to have high-risk disease according to the National Comprehensive Cancer Network IPI (P = .009) or CNS IPI (P = .01) and significantly more likely to have leptomeningeal disease only (P less than .001).
Treatment
CNS-intensive therapy was defined as any established multiagent IV chemotherapy regimen with two or more CNS-penetrating drugs and cytarabine, with or without intrathecal chemotherapy and/or radiotherapy.
CNS-conservative therapy was defined as one or fewer IV CNS-penetrating chemotherapy agents in induction, with or without intrathecal chemotherapy and/or radiotherapy.
Systemic induction in the CNS-intensive group consisted of R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with IV methotrexate and cytarabine) in 66% of patients and R-CODOX-M/IVAC (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine) in 24% of patients.
The most common systemic induction regimens in the CNS-conservative group were R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, given to 83% of patients.
CNS-directed IV therapy was given to 100% of the CNS-intensive group and 60% of the CNS-conservative group. This consisted of IV methotrexate plus cytarabine (97%) or MATRix (methotrexate, cytarabine, and thiotepa; 3%) in the CNS-intensive group and high-dose methotrexate in the conservative group.
Intrathecal chemotherapy was given to 97% of the CNS-intensive group and 60% of the CNS-conservative group. CNS-directed radiation was given to 32% and 19%, respectively.
Thirteen patients in the CNS-intensive group and one in the CNS-conservative group underwent autologous transplant as consolidation.
Outcomes
Dose reductions were more frequent in the CNS-conservative group than in the CNS-intensive group, at 48% and 18% (P = .009), as was early cessation of chemotherapy, at 52% and 18% (P = .002). Rates of treatment-related mortality were similar, at 13% in the CNS-intensive group and 12% in the CNS-conservative group.
At the end of induction, the complete response rate was 69% in the CNS-intensive group and 51% in the CNS-conservative group (P = .16). Primary refractory disease was observed in 19% and 38% of patients, respectively (P = .07).
The CNS was the most common site of relapse or progression (n = 28). CNS progression or relapse occurred in 25% of the CNS-intensive group and 49% of the CNS-conservative group (P = .03).
The 2-year progression-free survival rate was 50% for the CNS-intensive group and 31% for the CNS-conservative group (P = .006). The 2-year overall survival rate was 54% and 44%, respectively (P = .037).
When patients were matched for induction outcomes, consolidative transplant did not improve survival.
“The most significant factor affecting survival was the ability to control the CNS disease, which was improved by the addition of IV cytarabine to [high-dose methotrexate],” the researchers wrote.
“Whilst the younger age and more intensive systemic treatment of the CNS-intensive group may have contributed to the improved survival, it is clear that CNS disease control was substantially improved by the addition of cytarabine with lower rates of CNS relapse/progression observed.”
The researchers noted that “adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.”
There was no formal funding for this study, and the researchers did not provide financial disclosures.
SOURCE: Wight JC et al. Br J Haematol. 2019 Jun 24. doi: 10.1111/bjh.16064.
FROM BRITISH JOURNAL OF HAEMATOLOGY
Daratumumab wins new indication for newly diagnosed myeloma patients
Janssen’s daratumumab (Darzalex) has picked up a sixth adult multiple myeloma indication, this time in combination with lenalidomide (Revlimid) and dexamethasone in newly diagnosed patients ineligible for autologous stem cell transplants.
The phase 3 MAIA trial found that 97 of 368 patients (26.4%) treated with the combination – dubbed DRd – progressed or died at a median follow-up of 28 months, versus 143 of 269 (38.8%) treated with lenalidomide and dexamethasone alone (Rd). An estimated 55.6% of patients on lenalidomide and dexamethasone, versus 70.6% with the daratumumab add-on, were alive without progression at 30 months (N Engl J Med. 2019 May 30;380[22]:2104-15).
Previously approved indications for daratumumab include relapsed or refractory disease after at least one other therapy; and combination treatment with bortezomib, melphalan, and prednisone, also in newly diagnosed patients who are ineligible for transplant.
The most common grade 3 and 4 adverse events reported in the MAIA trial were neutropenia (50.0% for the DRd group versus 35.3% for the Rd group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
Janssen’s daratumumab (Darzalex) has picked up a sixth adult multiple myeloma indication, this time in combination with lenalidomide (Revlimid) and dexamethasone in newly diagnosed patients ineligible for autologous stem cell transplants.
The phase 3 MAIA trial found that 97 of 368 patients (26.4%) treated with the combination – dubbed DRd – progressed or died at a median follow-up of 28 months, versus 143 of 269 (38.8%) treated with lenalidomide and dexamethasone alone (Rd). An estimated 55.6% of patients on lenalidomide and dexamethasone, versus 70.6% with the daratumumab add-on, were alive without progression at 30 months (N Engl J Med. 2019 May 30;380[22]:2104-15).
Previously approved indications for daratumumab include relapsed or refractory disease after at least one other therapy; and combination treatment with bortezomib, melphalan, and prednisone, also in newly diagnosed patients who are ineligible for transplant.
The most common grade 3 and 4 adverse events reported in the MAIA trial were neutropenia (50.0% for the DRd group versus 35.3% for the Rd group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
Janssen’s daratumumab (Darzalex) has picked up a sixth adult multiple myeloma indication, this time in combination with lenalidomide (Revlimid) and dexamethasone in newly diagnosed patients ineligible for autologous stem cell transplants.
The phase 3 MAIA trial found that 97 of 368 patients (26.4%) treated with the combination – dubbed DRd – progressed or died at a median follow-up of 28 months, versus 143 of 269 (38.8%) treated with lenalidomide and dexamethasone alone (Rd). An estimated 55.6% of patients on lenalidomide and dexamethasone, versus 70.6% with the daratumumab add-on, were alive without progression at 30 months (N Engl J Med. 2019 May 30;380[22]:2104-15).
Previously approved indications for daratumumab include relapsed or refractory disease after at least one other therapy; and combination treatment with bortezomib, melphalan, and prednisone, also in newly diagnosed patients who are ineligible for transplant.
The most common grade 3 and 4 adverse events reported in the MAIA trial were neutropenia (50.0% for the DRd group versus 35.3% for the Rd group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
Cell count ratios appear to predict thromboembolism in lymphoma
AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.
A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.
“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.
To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.
The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).
Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.
A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).
“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”
Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.
The investigators reported no disclosures.
SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.
AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.
A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.
“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.
To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.
The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).
Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.
A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).
“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”
Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.
The investigators reported no disclosures.
SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.
AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.
A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.
“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.
To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.
The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).
Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.
A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).
“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”
Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.
The investigators reported no disclosures.
SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.
REPORTING FROM EHA CONGRESS
Partners in Oncology Care: Coordinated Follicular Lymphoma Management (FULL)
Four case examples illustrate the important role of multidisciplinary medical care for the optimal long-term care of patients with follicular lymphoma.
Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.
We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.3 This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.
In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.4 FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).5 HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.6
Case Example 1
A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A1c (HbA1c) 7 months prior was 5.6%.
Discussion
The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA1c > 6.1%, and body mass index > 30.7 This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.
Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.8 In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.9 Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid
Case Example 2
A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.
Discussion
Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.10 A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.
Case Example 3
A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.
As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.
Discussion
Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m2 are administered, or when combined with chest radiation.13 This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.14
Case Example 4
An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B12 deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.
Discussion
Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).15 A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).16 Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.17
Conclusion
As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.
1. Friedman EL, Chawla N, Morris PT, et al. Assessing the development of multidisciplinary care: experience of the National Cancer Institute community cancer centers program. J Oncol Pract. 2015;11(1):e36-e43.
2. Peterson K, Helfand M, Humphrey L, Christensen V, Carson S. Evidence brief: effectiveness of intensive primary care programs. https://www.hsrd.research.va.gov/publications/esp/Intensive-Primary-Care-Supplement.pdf. Published February 2013. Accessed April 5, 2019.
3. National Committee for Quality Assurance. Oncology medical home recognition. https://www.ncqa.org/programs/health-care-providers-practices/oncology-medical-home. Accessed April 5, 2019.
4. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055-2063.
5. Dulaney C, Wallace AS, Everett AS, Dover L, McDonald A, Kropp L. Defining health across the cancer continuum. Cureus. 2017;9(2):e1029.
6. Hopkins J, Mumber MP. Patient navigation through the cancer care continuum: an overview. J Oncol Pract. 2009;5(4):150-152.
7. Lee SY, Kurita N, Yokoyama Y, et al. Glucocorticoid-induced diabetes mellitus in patients with lymphoma treated with CHOP chemotherapy. Support Care Cancer. 2014;22(5):1385-1390.
8. McGill M, Blonde L, Juliana CN, et al; Global Partnership for Effective Diabetes Management. The interdisciplinary team in type 2 diabetes management: challenges and best practice solutions from real-world scenarios. J Clin Transl Endocrinol. 2017;7:21-27.
9. Horný M, Glover W, Gupte G, Saraswat A, Vimalananda V, Rosenzweig J. Patient navigation to improve diabetes outpatient care at a safety-net hospital: a retrospective cohort study. BMC Health Serv Res. 2017;17(1):759.
10. Reinwald M, Silva JT, Mueller NJ, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect. 2018;24(suppl 2):S53-S70.
11. Holle LM, Boehnke Michaud L. Oncology pharmacists in health care delivery: vital members of the cancer care team. J. Oncol. Pract. 2014;10(3):e142-e145.
12. Morgan KP, Muluneh B, Dean AM, Amerine LB. Impact of an integrated oral chemotherapy program on patient adherence. J Oncol Pharm Pract. 2018;24(5):332-336.
13. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869-2879.
14. Feltner C, Jones CD, Cené CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med. 2014;160(11):774-784.
15. Mora E, Smith EM, Donohoe C, Hertz DL. Vincristine-induced peripheral neuropathy in pediatric cancer patients. Am J Cancer Res. 2016;6(11):2416-2430.
16. Hershman DL, Lacchetti C, Dworkin RH, et al; American Society of Clinical Oncology. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(18):1941–1967
17. Duregon F, Vendramin B, Bullo V, et al. Effects of exercise on cancer patients suffering chemotherapy-induced peripheral neuropathy undergoing treatment: a systematic review. Crit Rev Oncol Hematol. 2018;121:90-100.
Four case examples illustrate the important role of multidisciplinary medical care for the optimal long-term care of patients with follicular lymphoma.
Four case examples illustrate the important role of multidisciplinary medical care for the optimal long-term care of patients with follicular lymphoma.
Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.
We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.3 This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.
In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.4 FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).5 HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.6
Case Example 1
A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A1c (HbA1c) 7 months prior was 5.6%.
Discussion
The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA1c > 6.1%, and body mass index > 30.7 This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.
Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.8 In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.9 Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid
Case Example 2
A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.
Discussion
Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.10 A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.
Case Example 3
A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.
As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.
Discussion
Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m2 are administered, or when combined with chest radiation.13 This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.14
Case Example 4
An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B12 deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.
Discussion
Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).15 A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).16 Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.17
Conclusion
As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.
Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.
We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.3 This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.
In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.4 FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).5 HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.6
Case Example 1
A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A1c (HbA1c) 7 months prior was 5.6%.
Discussion
The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA1c > 6.1%, and body mass index > 30.7 This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.
Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.8 In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.9 Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid
Case Example 2
A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.
Discussion
Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.10 A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.
Case Example 3
A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.
As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.
Discussion
Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m2 are administered, or when combined with chest radiation.13 This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.14
Case Example 4
An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B12 deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.
Discussion
Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).15 A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).16 Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.17
Conclusion
As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.
1. Friedman EL, Chawla N, Morris PT, et al. Assessing the development of multidisciplinary care: experience of the National Cancer Institute community cancer centers program. J Oncol Pract. 2015;11(1):e36-e43.
2. Peterson K, Helfand M, Humphrey L, Christensen V, Carson S. Evidence brief: effectiveness of intensive primary care programs. https://www.hsrd.research.va.gov/publications/esp/Intensive-Primary-Care-Supplement.pdf. Published February 2013. Accessed April 5, 2019.
3. National Committee for Quality Assurance. Oncology medical home recognition. https://www.ncqa.org/programs/health-care-providers-practices/oncology-medical-home. Accessed April 5, 2019.
4. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055-2063.
5. Dulaney C, Wallace AS, Everett AS, Dover L, McDonald A, Kropp L. Defining health across the cancer continuum. Cureus. 2017;9(2):e1029.
6. Hopkins J, Mumber MP. Patient navigation through the cancer care continuum: an overview. J Oncol Pract. 2009;5(4):150-152.
7. Lee SY, Kurita N, Yokoyama Y, et al. Glucocorticoid-induced diabetes mellitus in patients with lymphoma treated with CHOP chemotherapy. Support Care Cancer. 2014;22(5):1385-1390.
8. McGill M, Blonde L, Juliana CN, et al; Global Partnership for Effective Diabetes Management. The interdisciplinary team in type 2 diabetes management: challenges and best practice solutions from real-world scenarios. J Clin Transl Endocrinol. 2017;7:21-27.
9. Horný M, Glover W, Gupte G, Saraswat A, Vimalananda V, Rosenzweig J. Patient navigation to improve diabetes outpatient care at a safety-net hospital: a retrospective cohort study. BMC Health Serv Res. 2017;17(1):759.
10. Reinwald M, Silva JT, Mueller NJ, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect. 2018;24(suppl 2):S53-S70.
11. Holle LM, Boehnke Michaud L. Oncology pharmacists in health care delivery: vital members of the cancer care team. J. Oncol. Pract. 2014;10(3):e142-e145.
12. Morgan KP, Muluneh B, Dean AM, Amerine LB. Impact of an integrated oral chemotherapy program on patient adherence. J Oncol Pharm Pract. 2018;24(5):332-336.
13. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869-2879.
14. Feltner C, Jones CD, Cené CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med. 2014;160(11):774-784.
15. Mora E, Smith EM, Donohoe C, Hertz DL. Vincristine-induced peripheral neuropathy in pediatric cancer patients. Am J Cancer Res. 2016;6(11):2416-2430.
16. Hershman DL, Lacchetti C, Dworkin RH, et al; American Society of Clinical Oncology. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(18):1941–1967
17. Duregon F, Vendramin B, Bullo V, et al. Effects of exercise on cancer patients suffering chemotherapy-induced peripheral neuropathy undergoing treatment: a systematic review. Crit Rev Oncol Hematol. 2018;121:90-100.
1. Friedman EL, Chawla N, Morris PT, et al. Assessing the development of multidisciplinary care: experience of the National Cancer Institute community cancer centers program. J Oncol Pract. 2015;11(1):e36-e43.
2. Peterson K, Helfand M, Humphrey L, Christensen V, Carson S. Evidence brief: effectiveness of intensive primary care programs. https://www.hsrd.research.va.gov/publications/esp/Intensive-Primary-Care-Supplement.pdf. Published February 2013. Accessed April 5, 2019.
3. National Committee for Quality Assurance. Oncology medical home recognition. https://www.ncqa.org/programs/health-care-providers-practices/oncology-medical-home. Accessed April 5, 2019.
4. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055-2063.
5. Dulaney C, Wallace AS, Everett AS, Dover L, McDonald A, Kropp L. Defining health across the cancer continuum. Cureus. 2017;9(2):e1029.
6. Hopkins J, Mumber MP. Patient navigation through the cancer care continuum: an overview. J Oncol Pract. 2009;5(4):150-152.
7. Lee SY, Kurita N, Yokoyama Y, et al. Glucocorticoid-induced diabetes mellitus in patients with lymphoma treated with CHOP chemotherapy. Support Care Cancer. 2014;22(5):1385-1390.
8. McGill M, Blonde L, Juliana CN, et al; Global Partnership for Effective Diabetes Management. The interdisciplinary team in type 2 diabetes management: challenges and best practice solutions from real-world scenarios. J Clin Transl Endocrinol. 2017;7:21-27.
9. Horný M, Glover W, Gupte G, Saraswat A, Vimalananda V, Rosenzweig J. Patient navigation to improve diabetes outpatient care at a safety-net hospital: a retrospective cohort study. BMC Health Serv Res. 2017;17(1):759.
10. Reinwald M, Silva JT, Mueller NJ, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect. 2018;24(suppl 2):S53-S70.
11. Holle LM, Boehnke Michaud L. Oncology pharmacists in health care delivery: vital members of the cancer care team. J. Oncol. Pract. 2014;10(3):e142-e145.
12. Morgan KP, Muluneh B, Dean AM, Amerine LB. Impact of an integrated oral chemotherapy program on patient adherence. J Oncol Pharm Pract. 2018;24(5):332-336.
13. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869-2879.
14. Feltner C, Jones CD, Cené CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med. 2014;160(11):774-784.
15. Mora E, Smith EM, Donohoe C, Hertz DL. Vincristine-induced peripheral neuropathy in pediatric cancer patients. Am J Cancer Res. 2016;6(11):2416-2430.
16. Hershman DL, Lacchetti C, Dworkin RH, et al; American Society of Clinical Oncology. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(18):1941–1967
17. Duregon F, Vendramin B, Bullo V, et al. Effects of exercise on cancer patients suffering chemotherapy-induced peripheral neuropathy undergoing treatment: a systematic review. Crit Rev Oncol Hematol. 2018;121:90-100.
BET inhibitors may target oncogene in ABC-like DLBCL
(ABC-like DLBCL).
Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.
The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.
Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.
The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.
Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.
These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.
Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.
The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.
The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.
“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.
This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.
SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.
(ABC-like DLBCL).
Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.
The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.
Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.
The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.
Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.
These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.
Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.
The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.
The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.
“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.
This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.
SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.
(ABC-like DLBCL).
Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.
The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.
Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.
The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.
Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.
These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.
Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.
The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.
The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.
“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.
This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.
SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.
FROM SCIENCE TRANSLATIONAL MEDICINE
Bispecific CAR T-cell therapy yields complete responses in relapsed/refractory non-Hodgkin lymphomas
CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.
Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.
“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.
Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.
Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.
Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.
“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.
The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.
In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.
A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.
There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.
Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.
To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.
Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.
Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.
SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.
This article was updated on 7/8/2019
CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.
Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.
“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.
Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.
Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.
Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.
“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.
The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.
In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.
A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.
There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.
Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.
To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.
Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.
Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.
SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.
This article was updated on 7/8/2019
CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.
Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.
“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.
Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.
Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.
Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.
“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.
The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.
In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.
A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.
There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.
Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.
To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.
Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.
Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.
SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.
This article was updated on 7/8/2019
REPORTING FROM ASCO 2019