User login
DA-EPOCH-R appears more toxic than standard R-CHOP in DLBCL
The use of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) as upfront treatment in patients with diffuse large B-cell lymphoma (DLBCL) showed greater toxicity and did not improve progression-free survival versus standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), according to results from a phase 3 trial.
“Less favorable outcomes for patients with recurrent DLBCL prompted efforts to improve first-line approaches and biomarkers to identify high-risk patients,” wrote Nancy L. Bartlett, MD, of Washington University, St. Louis, and her colleagues wrote in the Journal of Clinical Oncology.
The Alliance/CALGB 50303 study included 491 patients with DLBCL who were randomized in a 1:1 fashion to receive DA-EPOCH-R or R-CHOP every 21 days for a total of six cycles. Dosing for the DA-EPOCH-R regimen was determined using absolute neutrophil and platelet counts.
The primary endpoint measured was progression-free survival (PFS); secondary endpoints included safety, overall survival (OS), and response rate.
After a median follow-up of 5.2 years, the researchers found no significant difference in PFS between the study arms (DA-EPOCH-R hazard ratio, 0.93; 95% confidence interval, 0.68-1.27; P = .65). Additionally, there was no significant difference in OS (HR, 1.09; 95% CI, 0.75-1.59; P = .64).
The overall response rate was 88.0% in the R-CHOP arm versus 86.7% in the DA-EPOCH-R arm (P = .67).
With respect to safety, grade 3 or 4 adverse events were more frequently seen in the DA-EPOCH-R group than in the R-CHOP group (P less than .001). These toxicities included febrile neutropenia, infections, neuropathy, and mucositis.
The researchers did see significantly improved PFS in the DA-EPOCH-R arm in post hoc subset analyses of patients with International Prognostic Index (IPI) 3-5, but the subset analysis “was unplanned and not powered” and the significance “must be tempered in light of multiple comparisons.”
“We now understand DLBCL is even more heterogeneous than appreciated when this trial was designed,” the researchers wrote. “Therefore, the National Clinical Trials Network is planning a precision medicine approach to identify molecular subsets of DLBCL and determine if specific chemotherapy platforms and/or targeted agents offer differential benefit.”
The study was supported by the National Cancer Institute. The authors reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Jazz Pharmaceuticals, Morphosys, and other companies.
SOURCE: Bartlett NL et al. J Clin Oncol. 2019 Apr 2. doi: 10.1200/JCO.18.01994.
The use of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) as upfront treatment in patients with diffuse large B-cell lymphoma (DLBCL) showed greater toxicity and did not improve progression-free survival versus standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), according to results from a phase 3 trial.
“Less favorable outcomes for patients with recurrent DLBCL prompted efforts to improve first-line approaches and biomarkers to identify high-risk patients,” wrote Nancy L. Bartlett, MD, of Washington University, St. Louis, and her colleagues wrote in the Journal of Clinical Oncology.
The Alliance/CALGB 50303 study included 491 patients with DLBCL who were randomized in a 1:1 fashion to receive DA-EPOCH-R or R-CHOP every 21 days for a total of six cycles. Dosing for the DA-EPOCH-R regimen was determined using absolute neutrophil and platelet counts.
The primary endpoint measured was progression-free survival (PFS); secondary endpoints included safety, overall survival (OS), and response rate.
After a median follow-up of 5.2 years, the researchers found no significant difference in PFS between the study arms (DA-EPOCH-R hazard ratio, 0.93; 95% confidence interval, 0.68-1.27; P = .65). Additionally, there was no significant difference in OS (HR, 1.09; 95% CI, 0.75-1.59; P = .64).
The overall response rate was 88.0% in the R-CHOP arm versus 86.7% in the DA-EPOCH-R arm (P = .67).
With respect to safety, grade 3 or 4 adverse events were more frequently seen in the DA-EPOCH-R group than in the R-CHOP group (P less than .001). These toxicities included febrile neutropenia, infections, neuropathy, and mucositis.
The researchers did see significantly improved PFS in the DA-EPOCH-R arm in post hoc subset analyses of patients with International Prognostic Index (IPI) 3-5, but the subset analysis “was unplanned and not powered” and the significance “must be tempered in light of multiple comparisons.”
“We now understand DLBCL is even more heterogeneous than appreciated when this trial was designed,” the researchers wrote. “Therefore, the National Clinical Trials Network is planning a precision medicine approach to identify molecular subsets of DLBCL and determine if specific chemotherapy platforms and/or targeted agents offer differential benefit.”
The study was supported by the National Cancer Institute. The authors reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Jazz Pharmaceuticals, Morphosys, and other companies.
SOURCE: Bartlett NL et al. J Clin Oncol. 2019 Apr 2. doi: 10.1200/JCO.18.01994.
The use of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) as upfront treatment in patients with diffuse large B-cell lymphoma (DLBCL) showed greater toxicity and did not improve progression-free survival versus standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), according to results from a phase 3 trial.
“Less favorable outcomes for patients with recurrent DLBCL prompted efforts to improve first-line approaches and biomarkers to identify high-risk patients,” wrote Nancy L. Bartlett, MD, of Washington University, St. Louis, and her colleagues wrote in the Journal of Clinical Oncology.
The Alliance/CALGB 50303 study included 491 patients with DLBCL who were randomized in a 1:1 fashion to receive DA-EPOCH-R or R-CHOP every 21 days for a total of six cycles. Dosing for the DA-EPOCH-R regimen was determined using absolute neutrophil and platelet counts.
The primary endpoint measured was progression-free survival (PFS); secondary endpoints included safety, overall survival (OS), and response rate.
After a median follow-up of 5.2 years, the researchers found no significant difference in PFS between the study arms (DA-EPOCH-R hazard ratio, 0.93; 95% confidence interval, 0.68-1.27; P = .65). Additionally, there was no significant difference in OS (HR, 1.09; 95% CI, 0.75-1.59; P = .64).
The overall response rate was 88.0% in the R-CHOP arm versus 86.7% in the DA-EPOCH-R arm (P = .67).
With respect to safety, grade 3 or 4 adverse events were more frequently seen in the DA-EPOCH-R group than in the R-CHOP group (P less than .001). These toxicities included febrile neutropenia, infections, neuropathy, and mucositis.
The researchers did see significantly improved PFS in the DA-EPOCH-R arm in post hoc subset analyses of patients with International Prognostic Index (IPI) 3-5, but the subset analysis “was unplanned and not powered” and the significance “must be tempered in light of multiple comparisons.”
“We now understand DLBCL is even more heterogeneous than appreciated when this trial was designed,” the researchers wrote. “Therefore, the National Clinical Trials Network is planning a precision medicine approach to identify molecular subsets of DLBCL and determine if specific chemotherapy platforms and/or targeted agents offer differential benefit.”
The study was supported by the National Cancer Institute. The authors reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Jazz Pharmaceuticals, Morphosys, and other companies.
SOURCE: Bartlett NL et al. J Clin Oncol. 2019 Apr 2. doi: 10.1200/JCO.18.01994.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Polatuzumab outperforms pinatuzumab in non-Hodgkin lymphoma
Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.
In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).
Researchers also observed a more favorable benefit-risk profile with R-pola.
Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.
The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m2 plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.
Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.
Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.
The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.
Response and survival
Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.
The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.
In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.
The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.
“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.
Safety
Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.
Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.
There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.
There were no fatal AEs in the other arms.
“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.
Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.
Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.
The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.
SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.
Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.
In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).
Researchers also observed a more favorable benefit-risk profile with R-pola.
Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.
The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m2 plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.
Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.
Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.
The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.
Response and survival
Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.
The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.
In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.
The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.
“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.
Safety
Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.
Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.
There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.
There were no fatal AEs in the other arms.
“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.
Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.
Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.
The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.
SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.
Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.
In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).
Researchers also observed a more favorable benefit-risk profile with R-pola.
Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.
The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m2 plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.
Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.
Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.
The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.
Response and survival
Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.
The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.
In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.
The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.
“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.
Safety
Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.
Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.
There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.
There were no fatal AEs in the other arms.
“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.
Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.
Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.
The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.
SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.
FROM LANCET HAEMATOLOGY
Early data support R-BAC for post-BTKi mantle cell lymphoma
GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.
Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.
This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.
Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.
Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.
All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m2 or 500 mg) on day 1, bendamustine 70 mg/m2 on days 1 and 2, and cytarabine 500 mg/m2 on days 1 through 3, given in a 28-day cycle.
Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.
Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.
Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.
For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).
The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.
The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.
Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”
During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.
“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”
The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.
In an interview, Dr. Rule added perspective to these findings.
“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”
However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.
Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.
He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”
With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.
The investigators reported having no conflicts of interest.
GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.
Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.
This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.
Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.
Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.
All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m2 or 500 mg) on day 1, bendamustine 70 mg/m2 on days 1 and 2, and cytarabine 500 mg/m2 on days 1 through 3, given in a 28-day cycle.
Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.
Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.
Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.
For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).
The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.
The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.
Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”
During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.
“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”
The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.
In an interview, Dr. Rule added perspective to these findings.
“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”
However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.
Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.
He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”
With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.
The investigators reported having no conflicts of interest.
GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.
Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.
This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.
Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.
Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.
All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m2 or 500 mg) on day 1, bendamustine 70 mg/m2 on days 1 and 2, and cytarabine 500 mg/m2 on days 1 through 3, given in a 28-day cycle.
Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.
Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.
Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.
For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).
The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.
The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.
Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”
During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.
“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”
The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.
In an interview, Dr. Rule added perspective to these findings.
“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”
However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.
Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.
He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”
With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.
The investigators reported having no conflicts of interest.
REPORTING FROM BSH 2019
ASCO, CCO issue multiple myeloma treatment guidelines
New clinical practice guidelines, jointly released by two leading cancer organizations, provide nearly 50 specific recommendations for the management of newly diagnosed and relapsed multiple myeloma patients.
The guidelines from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) were authored by a panel of 21 experts in medical oncology, surgery, radiation oncology, and advocacy who reviewed 124 relevant studies published between 2005 and 2018.
“The treatment of multiple myeloma has changed significantly in the last 5 years. Since 2015, four new drugs have been approved, thus providing more options and adding to the complexity of treatment options,” the expert panel wrote in the Journal of Clinical Oncology.
The recommendations are intended to put in context recent randomized trials and drug advances, according to the experts, led by cochairs Joseph Mikhael, MD, of City of Hope Cancer Center, Phoenix, and the International Myeloma Foundation, North Hollywood, Calif., and Tom Martin, MD, of the University of California, San Francisco.
Specifically, the recently approved agents include the proteasome inhibitor ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies daratumumab and elotuzumab, directed at CD38 and SLAMF7, respectively.
There are 20 specific recommendations for newly diagnosed, transplant-eligible patients with multiple myeloma; 10 recommendations for newly diagnosed, transplant-ineligible patients; and 16 recommendations related to relapsed disease in the ASCO/CCO guidelines.
All transplant-eligible patients should be offered up-front autologous stem cell transplant (ASCT), according to the guidelines. By contrast, allogeneic transplant is not routinely recommended but “may be considered” in select high-risk patients, and tandem transplant “should not be routinely recommended,” the expert panelists said in their report.
Lenalidomide maintenance therapy should be routinely offered to standard-risk, transplant-eligible patients, according to the panel, whereas bortezomib maintenance could be considered in those who are intolerant of lenalidomide or can’t receive that immunomodulatory drug.
“Evidence is emerging for the use of ixazomib as maintenance therapy and may also be considered,” the panel members said, citing the TOURMALINE-MM3 study results presented at the 2018 annual meeting of the American Society of Hematology and recently published in the Lancet.
Although minimal residual disease (MRD)–negative status is linked to improved outcomes, there is insufficient evidence that MRD can be used today to modify maintenance therapy based on depth of response in transplant-eligible patients, according to the guidelines. Likewise, in transplant-ineligible patients, MRD shouldn’t be used to guide treatment goals in clinical practice, the authors said.
Triplet therapies such as bortezomib, lenalidomide, and dexamethasone (VRd) can be considered for transplant ineligible patients, as can the combination of daratumumab and bortezomib plus melphalan and prednisone that was approved by the Food and Drug Administration in May 2018.
For patients with biochemically relapsed myeloma and high-risk disease – defined as early relapse and presence of high-risk cytogenetics – treatment should begin immediately, whereas close observation may be appropriate for patients with asymptomatic, slowly progressive relapse.
Triplets containing two novel therapies should be administered on first relapse, and should continue until disease progression, the expert panel advised.
If it was not already done after primary induction, ASCT should be offered to relapsed, transplant-eligible myeloma patients.
The expert panel reported numerous financial relationships with industry, including Celgene, Sanofi, AbbVie, TeneoBio, Roche, June Therapeutics, and others.
SOURCE: Mikhael J et al. J Clin Oncol. 2019 Apr 1. doi: 10.1200/JCO.18.02096.
New clinical practice guidelines, jointly released by two leading cancer organizations, provide nearly 50 specific recommendations for the management of newly diagnosed and relapsed multiple myeloma patients.
The guidelines from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) were authored by a panel of 21 experts in medical oncology, surgery, radiation oncology, and advocacy who reviewed 124 relevant studies published between 2005 and 2018.
“The treatment of multiple myeloma has changed significantly in the last 5 years. Since 2015, four new drugs have been approved, thus providing more options and adding to the complexity of treatment options,” the expert panel wrote in the Journal of Clinical Oncology.
The recommendations are intended to put in context recent randomized trials and drug advances, according to the experts, led by cochairs Joseph Mikhael, MD, of City of Hope Cancer Center, Phoenix, and the International Myeloma Foundation, North Hollywood, Calif., and Tom Martin, MD, of the University of California, San Francisco.
Specifically, the recently approved agents include the proteasome inhibitor ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies daratumumab and elotuzumab, directed at CD38 and SLAMF7, respectively.
There are 20 specific recommendations for newly diagnosed, transplant-eligible patients with multiple myeloma; 10 recommendations for newly diagnosed, transplant-ineligible patients; and 16 recommendations related to relapsed disease in the ASCO/CCO guidelines.
All transplant-eligible patients should be offered up-front autologous stem cell transplant (ASCT), according to the guidelines. By contrast, allogeneic transplant is not routinely recommended but “may be considered” in select high-risk patients, and tandem transplant “should not be routinely recommended,” the expert panelists said in their report.
Lenalidomide maintenance therapy should be routinely offered to standard-risk, transplant-eligible patients, according to the panel, whereas bortezomib maintenance could be considered in those who are intolerant of lenalidomide or can’t receive that immunomodulatory drug.
“Evidence is emerging for the use of ixazomib as maintenance therapy and may also be considered,” the panel members said, citing the TOURMALINE-MM3 study results presented at the 2018 annual meeting of the American Society of Hematology and recently published in the Lancet.
Although minimal residual disease (MRD)–negative status is linked to improved outcomes, there is insufficient evidence that MRD can be used today to modify maintenance therapy based on depth of response in transplant-eligible patients, according to the guidelines. Likewise, in transplant-ineligible patients, MRD shouldn’t be used to guide treatment goals in clinical practice, the authors said.
Triplet therapies such as bortezomib, lenalidomide, and dexamethasone (VRd) can be considered for transplant ineligible patients, as can the combination of daratumumab and bortezomib plus melphalan and prednisone that was approved by the Food and Drug Administration in May 2018.
For patients with biochemically relapsed myeloma and high-risk disease – defined as early relapse and presence of high-risk cytogenetics – treatment should begin immediately, whereas close observation may be appropriate for patients with asymptomatic, slowly progressive relapse.
Triplets containing two novel therapies should be administered on first relapse, and should continue until disease progression, the expert panel advised.
If it was not already done after primary induction, ASCT should be offered to relapsed, transplant-eligible myeloma patients.
The expert panel reported numerous financial relationships with industry, including Celgene, Sanofi, AbbVie, TeneoBio, Roche, June Therapeutics, and others.
SOURCE: Mikhael J et al. J Clin Oncol. 2019 Apr 1. doi: 10.1200/JCO.18.02096.
New clinical practice guidelines, jointly released by two leading cancer organizations, provide nearly 50 specific recommendations for the management of newly diagnosed and relapsed multiple myeloma patients.
The guidelines from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) were authored by a panel of 21 experts in medical oncology, surgery, radiation oncology, and advocacy who reviewed 124 relevant studies published between 2005 and 2018.
“The treatment of multiple myeloma has changed significantly in the last 5 years. Since 2015, four new drugs have been approved, thus providing more options and adding to the complexity of treatment options,” the expert panel wrote in the Journal of Clinical Oncology.
The recommendations are intended to put in context recent randomized trials and drug advances, according to the experts, led by cochairs Joseph Mikhael, MD, of City of Hope Cancer Center, Phoenix, and the International Myeloma Foundation, North Hollywood, Calif., and Tom Martin, MD, of the University of California, San Francisco.
Specifically, the recently approved agents include the proteasome inhibitor ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies daratumumab and elotuzumab, directed at CD38 and SLAMF7, respectively.
There are 20 specific recommendations for newly diagnosed, transplant-eligible patients with multiple myeloma; 10 recommendations for newly diagnosed, transplant-ineligible patients; and 16 recommendations related to relapsed disease in the ASCO/CCO guidelines.
All transplant-eligible patients should be offered up-front autologous stem cell transplant (ASCT), according to the guidelines. By contrast, allogeneic transplant is not routinely recommended but “may be considered” in select high-risk patients, and tandem transplant “should not be routinely recommended,” the expert panelists said in their report.
Lenalidomide maintenance therapy should be routinely offered to standard-risk, transplant-eligible patients, according to the panel, whereas bortezomib maintenance could be considered in those who are intolerant of lenalidomide or can’t receive that immunomodulatory drug.
“Evidence is emerging for the use of ixazomib as maintenance therapy and may also be considered,” the panel members said, citing the TOURMALINE-MM3 study results presented at the 2018 annual meeting of the American Society of Hematology and recently published in the Lancet.
Although minimal residual disease (MRD)–negative status is linked to improved outcomes, there is insufficient evidence that MRD can be used today to modify maintenance therapy based on depth of response in transplant-eligible patients, according to the guidelines. Likewise, in transplant-ineligible patients, MRD shouldn’t be used to guide treatment goals in clinical practice, the authors said.
Triplet therapies such as bortezomib, lenalidomide, and dexamethasone (VRd) can be considered for transplant ineligible patients, as can the combination of daratumumab and bortezomib plus melphalan and prednisone that was approved by the Food and Drug Administration in May 2018.
For patients with biochemically relapsed myeloma and high-risk disease – defined as early relapse and presence of high-risk cytogenetics – treatment should begin immediately, whereas close observation may be appropriate for patients with asymptomatic, slowly progressive relapse.
Triplets containing two novel therapies should be administered on first relapse, and should continue until disease progression, the expert panel advised.
If it was not already done after primary induction, ASCT should be offered to relapsed, transplant-eligible myeloma patients.
The expert panel reported numerous financial relationships with industry, including Celgene, Sanofi, AbbVie, TeneoBio, Roche, June Therapeutics, and others.
SOURCE: Mikhael J et al. J Clin Oncol. 2019 Apr 1. doi: 10.1200/JCO.18.02096.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Real world responses mirror TOURMALINE-MM1 data
Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.
Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).
Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”
This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.
“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.
In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.
The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.
About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).
Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.
Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.
Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.
Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.
“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”
When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.
However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.
“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.
The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.
SOURCE: Cook G et al. BSH 2019, Abstract OR-018.
Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.
Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).
Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”
This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.
“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.
In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.
The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.
About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).
Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.
Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.
Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.
Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.
“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”
When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.
However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.
“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.
The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.
SOURCE: Cook G et al. BSH 2019, Abstract OR-018.
Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.
Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).
Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”
This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.
“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.
In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.
The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.
About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).
Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.
Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.
Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.
Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.
“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”
When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.
However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.
“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.
The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.
SOURCE: Cook G et al. BSH 2019, Abstract OR-018.
Reporting from BSH 2019
Whole-genome sequencing demonstrates clinical relevance
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.
A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.
Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.
“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.
The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.
Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.
Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.
“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”
Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.
Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.
“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”
Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.
“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.
Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”
The study was sponsored by NHS England. The investigators reported having no conflicts of interest.
SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.
REPORTING FROM BSH 2019
Combo could replace standard conditioning regimen for myeloma
Busulfan plus melphalan could replace melphalan alone as the standard conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic cell transplant, according to researchers.
In a phase 3 trial, patients who received conditioning with busulfan plus melphalan had significantly longer median progression-free survival compared with patients who received melphalan alone – 64.7 months versus 43.5 months (P = .022).
However, there was no overall survival advantage with busulfan plus melphalan, and adverse events were more common with this regimen, reported Qaiser Bashir, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues. The report is in The Lancet Haematology.
To their knowledge, the researchers wrote, this was the first randomized, phase 3 trial showing a significant progression-free survival benefit for busulfan plus melphalan versus the standard of care of melphalan 200 mg/m2 pretransplantation conditioning. “These data suggest that busulfan plus melphalan conditioning can serve as a useful platform for further improvement of transplant outcomes in patients with myeloma.”
The current trial (NCT01413178) enrolled 205 multiple myeloma patients who were eligible for transplant. They were randomized to conditioning with melphalan alone or busulfan plus melphalan.
In all, 98 patients received melphalan alone, given at 200 mg/m2 on day –2. The 104 patients who received busulfan plus melphalan started with a test dose of busulfan at 32 mg/m2, which was followed by pharmacokinetically adjusted doses on days –7, –6, –5, and –4 to achieve a target daily area under the curve of 5,000 mmol/minute. These patients received melphalan at 70 mg/m2 per day on days –2 and –1.
The median age at transplant was 57.9 years (range, 31.7-70.9 years) in the busulfan group and 57.6 years (range, 34.3-70.6 years) in the melphalan-alone group.
The most common induction regimen used was bortezomib, lenalidomide, and dexamethasone, which was given to 60% of the busulfan group and 57% of the melphalan-alone group.
Most patients responded to induction – 96% of patients in the busulfan group and 94% of those in the melphalan-alone group.
There was no treatment-related mortality within 100 days of transplant.
At 90 days after transplant, the response rate was 98% in the busulfan group and 97% in the melphalan-alone group. The rate of complete remission/stringent complete remission was 27% and 34%, respectively.
Most patients received posttransplant maintenance. The most common maintenance regimen consisted of lenalidomide monotherapy, which was given to 57% of the busulfan group and 58% of the melphalan-alone group.
Patients continued maintenance until disease progression or unacceptable toxicity. The median duration of maintenance was 16.0 months in the busulfan group and 10.1 months in the melphalan-alone group.
The median follow-up was 22.6 months in the busulfan group and 20.2 months in the melphalan-alone group.
Progression-free survival was superior in the busulfan group. Median progression-free survival was 64.7 months in the busulfan group and 43.5 months in the melphalan-alone group (hazard ratio = 0.53; P = .022). The 3-year progression-free survival rate was 72% and 50%, respectively.
The median overall survival was not reached in either group. The 3-year overall survival rate was 91% in the busulfan group and 89% in the melphalan-alone group.
There were 10 deaths in the busulfan group, 7 due to progression and 3 due to infection. All 7 deaths in the melphalan-alone group were due to progression.
Grade 3-4 nonhematologic toxicity was more common in the busulfan group, occurring in 84% of that group and 33% of the melphalan-alone group (P less than .0001).
Grade 2-3 mucositis occurred in 74% of the busulfan group and 14% of the melphalan-alone group. There were no cases of grade 4 mucositis.
One patient in the busulfan group had grade 4 cardiac toxicity, an acute myocardial infarction, and ventricular fibrillation. However, the patient recovered and was in remission at last follow-up.
Two patients in the busulfan group developed second primary malignancies. One patient developed squamous cell skin cancer and rectal adenocarcinoma, and the other developed melanoma and basal cell skin carcinoma.
Three patients in the melphalan-alone group developed second primary malignancies. Two patients had squamous cell skin cancers and one had myelodysplastic syndrome.
Dr. Bashir and his colleagues noted that this study has limitations, including insufficient data to assess minimal residual disease and its impact on survival. It is a single-center study and induction and maintenance therapies were not prespecified.
“These results should be verified in a cooperative group or a multicenter, randomized study to assess the generalizability of our findings,” the researchers wrote.
Dr. Bashir and his colleagues reported having no competing financial interests. The trial was sponsored by MD Anderson Cancer Center in collaboration with Otsuka Pharmaceutical Development & Commercialization. The work was funded in part by the National Institutes of Health.
SOURCE: Bashir Q et al. Lancet Haematol. 2019 Mar 22. doi: 10.1016/S2352-3026(19)30023-7.
Busulfan plus melphalan could replace melphalan alone as the standard conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic cell transplant, according to researchers.
In a phase 3 trial, patients who received conditioning with busulfan plus melphalan had significantly longer median progression-free survival compared with patients who received melphalan alone – 64.7 months versus 43.5 months (P = .022).
However, there was no overall survival advantage with busulfan plus melphalan, and adverse events were more common with this regimen, reported Qaiser Bashir, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues. The report is in The Lancet Haematology.
To their knowledge, the researchers wrote, this was the first randomized, phase 3 trial showing a significant progression-free survival benefit for busulfan plus melphalan versus the standard of care of melphalan 200 mg/m2 pretransplantation conditioning. “These data suggest that busulfan plus melphalan conditioning can serve as a useful platform for further improvement of transplant outcomes in patients with myeloma.”
The current trial (NCT01413178) enrolled 205 multiple myeloma patients who were eligible for transplant. They were randomized to conditioning with melphalan alone or busulfan plus melphalan.
In all, 98 patients received melphalan alone, given at 200 mg/m2 on day –2. The 104 patients who received busulfan plus melphalan started with a test dose of busulfan at 32 mg/m2, which was followed by pharmacokinetically adjusted doses on days –7, –6, –5, and –4 to achieve a target daily area under the curve of 5,000 mmol/minute. These patients received melphalan at 70 mg/m2 per day on days –2 and –1.
The median age at transplant was 57.9 years (range, 31.7-70.9 years) in the busulfan group and 57.6 years (range, 34.3-70.6 years) in the melphalan-alone group.
The most common induction regimen used was bortezomib, lenalidomide, and dexamethasone, which was given to 60% of the busulfan group and 57% of the melphalan-alone group.
Most patients responded to induction – 96% of patients in the busulfan group and 94% of those in the melphalan-alone group.
There was no treatment-related mortality within 100 days of transplant.
At 90 days after transplant, the response rate was 98% in the busulfan group and 97% in the melphalan-alone group. The rate of complete remission/stringent complete remission was 27% and 34%, respectively.
Most patients received posttransplant maintenance. The most common maintenance regimen consisted of lenalidomide monotherapy, which was given to 57% of the busulfan group and 58% of the melphalan-alone group.
Patients continued maintenance until disease progression or unacceptable toxicity. The median duration of maintenance was 16.0 months in the busulfan group and 10.1 months in the melphalan-alone group.
The median follow-up was 22.6 months in the busulfan group and 20.2 months in the melphalan-alone group.
Progression-free survival was superior in the busulfan group. Median progression-free survival was 64.7 months in the busulfan group and 43.5 months in the melphalan-alone group (hazard ratio = 0.53; P = .022). The 3-year progression-free survival rate was 72% and 50%, respectively.
The median overall survival was not reached in either group. The 3-year overall survival rate was 91% in the busulfan group and 89% in the melphalan-alone group.
There were 10 deaths in the busulfan group, 7 due to progression and 3 due to infection. All 7 deaths in the melphalan-alone group were due to progression.
Grade 3-4 nonhematologic toxicity was more common in the busulfan group, occurring in 84% of that group and 33% of the melphalan-alone group (P less than .0001).
Grade 2-3 mucositis occurred in 74% of the busulfan group and 14% of the melphalan-alone group. There were no cases of grade 4 mucositis.
One patient in the busulfan group had grade 4 cardiac toxicity, an acute myocardial infarction, and ventricular fibrillation. However, the patient recovered and was in remission at last follow-up.
Two patients in the busulfan group developed second primary malignancies. One patient developed squamous cell skin cancer and rectal adenocarcinoma, and the other developed melanoma and basal cell skin carcinoma.
Three patients in the melphalan-alone group developed second primary malignancies. Two patients had squamous cell skin cancers and one had myelodysplastic syndrome.
Dr. Bashir and his colleagues noted that this study has limitations, including insufficient data to assess minimal residual disease and its impact on survival. It is a single-center study and induction and maintenance therapies were not prespecified.
“These results should be verified in a cooperative group or a multicenter, randomized study to assess the generalizability of our findings,” the researchers wrote.
Dr. Bashir and his colleagues reported having no competing financial interests. The trial was sponsored by MD Anderson Cancer Center in collaboration with Otsuka Pharmaceutical Development & Commercialization. The work was funded in part by the National Institutes of Health.
SOURCE: Bashir Q et al. Lancet Haematol. 2019 Mar 22. doi: 10.1016/S2352-3026(19)30023-7.
Busulfan plus melphalan could replace melphalan alone as the standard conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic cell transplant, according to researchers.
In a phase 3 trial, patients who received conditioning with busulfan plus melphalan had significantly longer median progression-free survival compared with patients who received melphalan alone – 64.7 months versus 43.5 months (P = .022).
However, there was no overall survival advantage with busulfan plus melphalan, and adverse events were more common with this regimen, reported Qaiser Bashir, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues. The report is in The Lancet Haematology.
To their knowledge, the researchers wrote, this was the first randomized, phase 3 trial showing a significant progression-free survival benefit for busulfan plus melphalan versus the standard of care of melphalan 200 mg/m2 pretransplantation conditioning. “These data suggest that busulfan plus melphalan conditioning can serve as a useful platform for further improvement of transplant outcomes in patients with myeloma.”
The current trial (NCT01413178) enrolled 205 multiple myeloma patients who were eligible for transplant. They were randomized to conditioning with melphalan alone or busulfan plus melphalan.
In all, 98 patients received melphalan alone, given at 200 mg/m2 on day –2. The 104 patients who received busulfan plus melphalan started with a test dose of busulfan at 32 mg/m2, which was followed by pharmacokinetically adjusted doses on days –7, –6, –5, and –4 to achieve a target daily area under the curve of 5,000 mmol/minute. These patients received melphalan at 70 mg/m2 per day on days –2 and –1.
The median age at transplant was 57.9 years (range, 31.7-70.9 years) in the busulfan group and 57.6 years (range, 34.3-70.6 years) in the melphalan-alone group.
The most common induction regimen used was bortezomib, lenalidomide, and dexamethasone, which was given to 60% of the busulfan group and 57% of the melphalan-alone group.
Most patients responded to induction – 96% of patients in the busulfan group and 94% of those in the melphalan-alone group.
There was no treatment-related mortality within 100 days of transplant.
At 90 days after transplant, the response rate was 98% in the busulfan group and 97% in the melphalan-alone group. The rate of complete remission/stringent complete remission was 27% and 34%, respectively.
Most patients received posttransplant maintenance. The most common maintenance regimen consisted of lenalidomide monotherapy, which was given to 57% of the busulfan group and 58% of the melphalan-alone group.
Patients continued maintenance until disease progression or unacceptable toxicity. The median duration of maintenance was 16.0 months in the busulfan group and 10.1 months in the melphalan-alone group.
The median follow-up was 22.6 months in the busulfan group and 20.2 months in the melphalan-alone group.
Progression-free survival was superior in the busulfan group. Median progression-free survival was 64.7 months in the busulfan group and 43.5 months in the melphalan-alone group (hazard ratio = 0.53; P = .022). The 3-year progression-free survival rate was 72% and 50%, respectively.
The median overall survival was not reached in either group. The 3-year overall survival rate was 91% in the busulfan group and 89% in the melphalan-alone group.
There were 10 deaths in the busulfan group, 7 due to progression and 3 due to infection. All 7 deaths in the melphalan-alone group were due to progression.
Grade 3-4 nonhematologic toxicity was more common in the busulfan group, occurring in 84% of that group and 33% of the melphalan-alone group (P less than .0001).
Grade 2-3 mucositis occurred in 74% of the busulfan group and 14% of the melphalan-alone group. There were no cases of grade 4 mucositis.
One patient in the busulfan group had grade 4 cardiac toxicity, an acute myocardial infarction, and ventricular fibrillation. However, the patient recovered and was in remission at last follow-up.
Two patients in the busulfan group developed second primary malignancies. One patient developed squamous cell skin cancer and rectal adenocarcinoma, and the other developed melanoma and basal cell skin carcinoma.
Three patients in the melphalan-alone group developed second primary malignancies. Two patients had squamous cell skin cancers and one had myelodysplastic syndrome.
Dr. Bashir and his colleagues noted that this study has limitations, including insufficient data to assess minimal residual disease and its impact on survival. It is a single-center study and induction and maintenance therapies were not prespecified.
“These results should be verified in a cooperative group or a multicenter, randomized study to assess the generalizability of our findings,” the researchers wrote.
Dr. Bashir and his colleagues reported having no competing financial interests. The trial was sponsored by MD Anderson Cancer Center in collaboration with Otsuka Pharmaceutical Development & Commercialization. The work was funded in part by the National Institutes of Health.
SOURCE: Bashir Q et al. Lancet Haematol. 2019 Mar 22. doi: 10.1016/S2352-3026(19)30023-7.
FROM LANCET HAEMATOLOGY
Novel assay unable to predict clinical severity in type 1 VWD
A novel whole blood assay was unable to predict clinical severity in patients with type 1 von Willebrand disease (VWD).
The whole blood ristocetin-induced platelet agglutination (WB-RIPA) assay has shown potential for use as a diagnostic test for patients with type 1 VWD. However, the ability of the assay to predict clinical severity of the disease is unknown.
Yuto Nakajima, MD, of the Nara (Japan) Medical University and his colleagues studied the diagnostic and clinical capabilities of the assay in 55 patients with type 1 VWD and 20 healthy controls. The results of the study were published in Haemophilia.
The team examined relationships between WB-RIPA levels, VWF-associated measurements, and bleeding scores using whole blood samples. Bleeding severity was assessed using scores from a standardized assessment tool.
After analysis, the team found that assay values were significantly lower in patients with type 1 VWD versus healthy controls (P less than .0001), which validated the detection abilities of the test.
However, correlations between WB-RIPA levels and specific VWF-associated measurements were found to be weak. Similar results were reported with assay levels and bleeding scores. There were no significant differences seen in WB-RIPA between patients with a bleeding score of 4 or greater (abnormal bleeding tendency) and less than 4 (no abnormal bleeding tendency).
“Our study indicated that the WB-RIPA assay would not be useful for assessing and predicting the clinical severity in type 1 VWD,” they wrote.
The authors acknowledged that a key limitation was that the definition of type 1 VWD used in the study was not based on the most current classification.
The study was supported by grant funding from the Ministry of Education, Culture, Sports, Science and Technology (Japan). The authors reported having no conflicts of interest.
SOURCE: Nakajima Y et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13725.
A novel whole blood assay was unable to predict clinical severity in patients with type 1 von Willebrand disease (VWD).
The whole blood ristocetin-induced platelet agglutination (WB-RIPA) assay has shown potential for use as a diagnostic test for patients with type 1 VWD. However, the ability of the assay to predict clinical severity of the disease is unknown.
Yuto Nakajima, MD, of the Nara (Japan) Medical University and his colleagues studied the diagnostic and clinical capabilities of the assay in 55 patients with type 1 VWD and 20 healthy controls. The results of the study were published in Haemophilia.
The team examined relationships between WB-RIPA levels, VWF-associated measurements, and bleeding scores using whole blood samples. Bleeding severity was assessed using scores from a standardized assessment tool.
After analysis, the team found that assay values were significantly lower in patients with type 1 VWD versus healthy controls (P less than .0001), which validated the detection abilities of the test.
However, correlations between WB-RIPA levels and specific VWF-associated measurements were found to be weak. Similar results were reported with assay levels and bleeding scores. There were no significant differences seen in WB-RIPA between patients with a bleeding score of 4 or greater (abnormal bleeding tendency) and less than 4 (no abnormal bleeding tendency).
“Our study indicated that the WB-RIPA assay would not be useful for assessing and predicting the clinical severity in type 1 VWD,” they wrote.
The authors acknowledged that a key limitation was that the definition of type 1 VWD used in the study was not based on the most current classification.
The study was supported by grant funding from the Ministry of Education, Culture, Sports, Science and Technology (Japan). The authors reported having no conflicts of interest.
SOURCE: Nakajima Y et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13725.
A novel whole blood assay was unable to predict clinical severity in patients with type 1 von Willebrand disease (VWD).
The whole blood ristocetin-induced platelet agglutination (WB-RIPA) assay has shown potential for use as a diagnostic test for patients with type 1 VWD. However, the ability of the assay to predict clinical severity of the disease is unknown.
Yuto Nakajima, MD, of the Nara (Japan) Medical University and his colleagues studied the diagnostic and clinical capabilities of the assay in 55 patients with type 1 VWD and 20 healthy controls. The results of the study were published in Haemophilia.
The team examined relationships between WB-RIPA levels, VWF-associated measurements, and bleeding scores using whole blood samples. Bleeding severity was assessed using scores from a standardized assessment tool.
After analysis, the team found that assay values were significantly lower in patients with type 1 VWD versus healthy controls (P less than .0001), which validated the detection abilities of the test.
However, correlations between WB-RIPA levels and specific VWF-associated measurements were found to be weak. Similar results were reported with assay levels and bleeding scores. There were no significant differences seen in WB-RIPA between patients with a bleeding score of 4 or greater (abnormal bleeding tendency) and less than 4 (no abnormal bleeding tendency).
“Our study indicated that the WB-RIPA assay would not be useful for assessing and predicting the clinical severity in type 1 VWD,” they wrote.
The authors acknowledged that a key limitation was that the definition of type 1 VWD used in the study was not based on the most current classification.
The study was supported by grant funding from the Ministry of Education, Culture, Sports, Science and Technology (Japan). The authors reported having no conflicts of interest.
SOURCE: Nakajima Y et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13725.
FROM HAEMOPHILIA
PK analysis shows benefit for rFVIII product in hemophilia A
Switching from the sucrose‐formulated recombinant factor VIII replacement therapy rFVIII‐FS (Kogenate) to the rFVIII product BAY 81‐8973 (Kovaltry) resulted in a longer half-life and improved bleeding rates in patients with hemophilia A, according to a recent report.
Juan Eduardo Megías‐Vericat, PharmD, of the Hospital Universitari i Politècnic La Fe, Valencia, Spain, and his colleagues conducted a comparative, cross‐sectional, pharmacokinetic analysis of switching from rFVIII‐FS to BAY 81‐8973 in patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.
“All the patients of this cohort were switched in a short period of time, while maintaining the same dose and frequency of infusions,” the researchers wrote.
The study included 14 patients who had moderate (n = 3) or severe (n = 11) hemophilia A and received pharmacokinetic-guided prophylaxis with rFVIII. The median weekly doses were 60.6 IU/kg and 61.6 IU/kg for rFVIII‐FS and BAY 81‐8973, respectively.
After analysis, the researchers found that the half-life of BAY 81‐8973 was significantly longer than rFVIII‐FS (median half-life, 16.9 hours vs. 15.4 hours; P = .001), with a median improvement of 3.0 hours (range, 1.5-4.0 hours). No significant differences were seen in any other pharmacokinetic factors.
With respect to bleeding, significant reductions were seen in annualized joint bleeding rate (P = .021), annualized bleeding rate (P = .038), and the number of spontaneous bleeds (P = .028) after the switch to BAY 81-8973.
The researchers acknowledged that the external validity of the study was a key limitation. As a result, Dr. Megías‐Vericat and his colleagues recommended that the findings be interpreted with discretion.
“The results of this study should be validated with an independent and larger cohort of patients, analyzing also the differences between adult and pediatric patients,” they concluded.
The study was partially funded by an unrestricted grant from Bayer. The authors reported having no conflicts of interest.
SOURCE: Megías-Vericat JE et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13733.
Switching from the sucrose‐formulated recombinant factor VIII replacement therapy rFVIII‐FS (Kogenate) to the rFVIII product BAY 81‐8973 (Kovaltry) resulted in a longer half-life and improved bleeding rates in patients with hemophilia A, according to a recent report.
Juan Eduardo Megías‐Vericat, PharmD, of the Hospital Universitari i Politècnic La Fe, Valencia, Spain, and his colleagues conducted a comparative, cross‐sectional, pharmacokinetic analysis of switching from rFVIII‐FS to BAY 81‐8973 in patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.
“All the patients of this cohort were switched in a short period of time, while maintaining the same dose and frequency of infusions,” the researchers wrote.
The study included 14 patients who had moderate (n = 3) or severe (n = 11) hemophilia A and received pharmacokinetic-guided prophylaxis with rFVIII. The median weekly doses were 60.6 IU/kg and 61.6 IU/kg for rFVIII‐FS and BAY 81‐8973, respectively.
After analysis, the researchers found that the half-life of BAY 81‐8973 was significantly longer than rFVIII‐FS (median half-life, 16.9 hours vs. 15.4 hours; P = .001), with a median improvement of 3.0 hours (range, 1.5-4.0 hours). No significant differences were seen in any other pharmacokinetic factors.
With respect to bleeding, significant reductions were seen in annualized joint bleeding rate (P = .021), annualized bleeding rate (P = .038), and the number of spontaneous bleeds (P = .028) after the switch to BAY 81-8973.
The researchers acknowledged that the external validity of the study was a key limitation. As a result, Dr. Megías‐Vericat and his colleagues recommended that the findings be interpreted with discretion.
“The results of this study should be validated with an independent and larger cohort of patients, analyzing also the differences between adult and pediatric patients,” they concluded.
The study was partially funded by an unrestricted grant from Bayer. The authors reported having no conflicts of interest.
SOURCE: Megías-Vericat JE et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13733.
Switching from the sucrose‐formulated recombinant factor VIII replacement therapy rFVIII‐FS (Kogenate) to the rFVIII product BAY 81‐8973 (Kovaltry) resulted in a longer half-life and improved bleeding rates in patients with hemophilia A, according to a recent report.
Juan Eduardo Megías‐Vericat, PharmD, of the Hospital Universitari i Politècnic La Fe, Valencia, Spain, and his colleagues conducted a comparative, cross‐sectional, pharmacokinetic analysis of switching from rFVIII‐FS to BAY 81‐8973 in patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.
“All the patients of this cohort were switched in a short period of time, while maintaining the same dose and frequency of infusions,” the researchers wrote.
The study included 14 patients who had moderate (n = 3) or severe (n = 11) hemophilia A and received pharmacokinetic-guided prophylaxis with rFVIII. The median weekly doses were 60.6 IU/kg and 61.6 IU/kg for rFVIII‐FS and BAY 81‐8973, respectively.
After analysis, the researchers found that the half-life of BAY 81‐8973 was significantly longer than rFVIII‐FS (median half-life, 16.9 hours vs. 15.4 hours; P = .001), with a median improvement of 3.0 hours (range, 1.5-4.0 hours). No significant differences were seen in any other pharmacokinetic factors.
With respect to bleeding, significant reductions were seen in annualized joint bleeding rate (P = .021), annualized bleeding rate (P = .038), and the number of spontaneous bleeds (P = .028) after the switch to BAY 81-8973.
The researchers acknowledged that the external validity of the study was a key limitation. As a result, Dr. Megías‐Vericat and his colleagues recommended that the findings be interpreted with discretion.
“The results of this study should be validated with an independent and larger cohort of patients, analyzing also the differences between adult and pediatric patients,” they concluded.
The study was partially funded by an unrestricted grant from Bayer. The authors reported having no conflicts of interest.
SOURCE: Megías-Vericat JE et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13733.
FROM HAEMOPHILIA
Prophylaxis maintains high FIX trough levels in hemophilia B
The recombinant factor IX (FIX) product rIX‐FP (albutrepenonacog alfa) can maintain high steady‐state FIX trough levels in both adult and pediatric patients with severe hemophilia B, according to a pharmacokinetic study.
“rIX‐FP is a fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin and has an extended half‐life compared with standard products, allowing a prolonged dosing interval,” wrote Joan C. Gill, MD, of the Medical College of Wisconsin, Milwaukee, along with her colleagues. The findings of the study were published in Haemophilia.
Safety and efficacy of rIX-FP was previously demonstrated for both adults/adolescents and children in two phase 3 trials. In the current analysis, the researchers evaluated mean steady state and observed trough FIX:C levels during prophylaxis with rIX-FP in the two previous trials and assessed the impact on hemophilia B patients.
The researchers studied 90 patients with severe hemophilia B, which included both adult/adolescent (n = 63) and pediatric (n = 27) patients. The adult/adolescent group was administered 35‐50 IU/kg or 50‐75 IU/kg of rIX‐FP every 7 and 10 or 14 days, respectively, while pediatric participants (younger than 12 years old) were given 35‐50 IU/kg of rIX‐FP every 7 days. Only the 7‐ and 14‐day dosing intervals were included in the analysis.
After analysis, the researchers reported that steady‐state FIX trough levels were higher than 5% across all doses in 96.2% and 97.9% of adult/adolescent and pediatric patients, respectively.
Among adults/adolescents, including all dose levels, the mean FIX:C trough levels were 22.26% for 7-day regimens and 12.48% for 14-day regimens. Among children in the study, the mean steady-state FIX:C trough level was 12.80%.
The team reported that these results, which are consistent with low median annualized bleeding rates observed, indicate that sustaining high FIX trough levels may successfully change a case of severe disease into a mild bleeding phenotype.
The authors acknowledged a key limitation of the study was the unknown effects of rIX‐FP remaining within the extravascular space. Further biodistribution studies are required to fully understand these effects.
“Patients may find that an extended dosing regimen would still provide protection from bleeds but be easier to maintain,” they concluded.
The study was funded by CSL Behring. The authors reported financial disclosures related to Bayer, CSL Behring, Kedrion Biopharma, Novo Nordisk, Pfizer, and others.
SOURCE: Gill JC et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13735.
The recombinant factor IX (FIX) product rIX‐FP (albutrepenonacog alfa) can maintain high steady‐state FIX trough levels in both adult and pediatric patients with severe hemophilia B, according to a pharmacokinetic study.
“rIX‐FP is a fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin and has an extended half‐life compared with standard products, allowing a prolonged dosing interval,” wrote Joan C. Gill, MD, of the Medical College of Wisconsin, Milwaukee, along with her colleagues. The findings of the study were published in Haemophilia.
Safety and efficacy of rIX-FP was previously demonstrated for both adults/adolescents and children in two phase 3 trials. In the current analysis, the researchers evaluated mean steady state and observed trough FIX:C levels during prophylaxis with rIX-FP in the two previous trials and assessed the impact on hemophilia B patients.
The researchers studied 90 patients with severe hemophilia B, which included both adult/adolescent (n = 63) and pediatric (n = 27) patients. The adult/adolescent group was administered 35‐50 IU/kg or 50‐75 IU/kg of rIX‐FP every 7 and 10 or 14 days, respectively, while pediatric participants (younger than 12 years old) were given 35‐50 IU/kg of rIX‐FP every 7 days. Only the 7‐ and 14‐day dosing intervals were included in the analysis.
After analysis, the researchers reported that steady‐state FIX trough levels were higher than 5% across all doses in 96.2% and 97.9% of adult/adolescent and pediatric patients, respectively.
Among adults/adolescents, including all dose levels, the mean FIX:C trough levels were 22.26% for 7-day regimens and 12.48% for 14-day regimens. Among children in the study, the mean steady-state FIX:C trough level was 12.80%.
The team reported that these results, which are consistent with low median annualized bleeding rates observed, indicate that sustaining high FIX trough levels may successfully change a case of severe disease into a mild bleeding phenotype.
The authors acknowledged a key limitation of the study was the unknown effects of rIX‐FP remaining within the extravascular space. Further biodistribution studies are required to fully understand these effects.
“Patients may find that an extended dosing regimen would still provide protection from bleeds but be easier to maintain,” they concluded.
The study was funded by CSL Behring. The authors reported financial disclosures related to Bayer, CSL Behring, Kedrion Biopharma, Novo Nordisk, Pfizer, and others.
SOURCE: Gill JC et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13735.
The recombinant factor IX (FIX) product rIX‐FP (albutrepenonacog alfa) can maintain high steady‐state FIX trough levels in both adult and pediatric patients with severe hemophilia B, according to a pharmacokinetic study.
“rIX‐FP is a fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin and has an extended half‐life compared with standard products, allowing a prolonged dosing interval,” wrote Joan C. Gill, MD, of the Medical College of Wisconsin, Milwaukee, along with her colleagues. The findings of the study were published in Haemophilia.
Safety and efficacy of rIX-FP was previously demonstrated for both adults/adolescents and children in two phase 3 trials. In the current analysis, the researchers evaluated mean steady state and observed trough FIX:C levels during prophylaxis with rIX-FP in the two previous trials and assessed the impact on hemophilia B patients.
The researchers studied 90 patients with severe hemophilia B, which included both adult/adolescent (n = 63) and pediatric (n = 27) patients. The adult/adolescent group was administered 35‐50 IU/kg or 50‐75 IU/kg of rIX‐FP every 7 and 10 or 14 days, respectively, while pediatric participants (younger than 12 years old) were given 35‐50 IU/kg of rIX‐FP every 7 days. Only the 7‐ and 14‐day dosing intervals were included in the analysis.
After analysis, the researchers reported that steady‐state FIX trough levels were higher than 5% across all doses in 96.2% and 97.9% of adult/adolescent and pediatric patients, respectively.
Among adults/adolescents, including all dose levels, the mean FIX:C trough levels were 22.26% for 7-day regimens and 12.48% for 14-day regimens. Among children in the study, the mean steady-state FIX:C trough level was 12.80%.
The team reported that these results, which are consistent with low median annualized bleeding rates observed, indicate that sustaining high FIX trough levels may successfully change a case of severe disease into a mild bleeding phenotype.
The authors acknowledged a key limitation of the study was the unknown effects of rIX‐FP remaining within the extravascular space. Further biodistribution studies are required to fully understand these effects.
“Patients may find that an extended dosing regimen would still provide protection from bleeds but be easier to maintain,” they concluded.
The study was funded by CSL Behring. The authors reported financial disclosures related to Bayer, CSL Behring, Kedrion Biopharma, Novo Nordisk, Pfizer, and others.
SOURCE: Gill JC et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13735.
FROM HAEMOPHILIA