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Evaluation of Fitness, Metabolism, and Quality of Life During Hematopoietic Stem Cell Transplant
Purpose: The objective of this study is to characterize biochemical and physiologic factors that contribute to changes in patient fitness, body composition, and quality of life (QoL) during hematopoietic stem cell transplantation (HCT).
Background: Though HCT can cure subsets of patients with hematologic malignancies, it carries a high risk of short- and long-term toxicity. Prior work has shown that following both autologous and allogeneic HCT, most patients suffer impairment in QoL for many months after transplant. Efforts to date have inconsistently demonstrated benefit in addressing parameters of nutrition, physical activity, and metabolism.
Methods: This prospective pilot study of 60 patients at VA Puget Sound Marrow Transplant Unit with hematologic malignancy will incorporate multidisciplinary evaluation by endocrinology, nutrition, gastroenterology, and oncology specialties. Assessments before and periodically after HCT include objective measures of fitness by 6-minue walk test, resting energy expenditure, maximum oxygen consumption, handgrip and other muscle group strength, and stair climbing power; body composition by bio-impedance and dual-energy X-ray absorptiometry scans; anabolic and catabolic factors such as insulin growth factor-1, growth hormone, and free and weakly bound testosterone; biochemical markers of inflammatory milieu; and validated questionnaires of nutrition, functional status, and QoL.
Results: The protocol opened to accrual in March 2017. To date, 12 patients have enrolled in study, and posttransplant evaluations (approximately 30 days after transplantation, median = 36) have been performed on 4. Early findings suggest relatively preserved body weight and composition but trends toward decreased QoL and fitness, particularly in aerobic capacity, handgrip strength, and total lower body fitness. Updated findings will be presented at the Association of VA Hematology/Oncology Conference.
Implications: With improving survival outcomes following HCT for hematologic malignancies due to advances in therapeutics and supportive care, increased attention will be directed at optimizing patient-centered quality outcomes. Understanding of the biochemical and physiologic factors underlying these outcomes may lead to refinements in prognostic models and present targets for risk mitigation interventions in the peri-transplant period.
Purpose: The objective of this study is to characterize biochemical and physiologic factors that contribute to changes in patient fitness, body composition, and quality of life (QoL) during hematopoietic stem cell transplantation (HCT).
Background: Though HCT can cure subsets of patients with hematologic malignancies, it carries a high risk of short- and long-term toxicity. Prior work has shown that following both autologous and allogeneic HCT, most patients suffer impairment in QoL for many months after transplant. Efforts to date have inconsistently demonstrated benefit in addressing parameters of nutrition, physical activity, and metabolism.
Methods: This prospective pilot study of 60 patients at VA Puget Sound Marrow Transplant Unit with hematologic malignancy will incorporate multidisciplinary evaluation by endocrinology, nutrition, gastroenterology, and oncology specialties. Assessments before and periodically after HCT include objective measures of fitness by 6-minue walk test, resting energy expenditure, maximum oxygen consumption, handgrip and other muscle group strength, and stair climbing power; body composition by bio-impedance and dual-energy X-ray absorptiometry scans; anabolic and catabolic factors such as insulin growth factor-1, growth hormone, and free and weakly bound testosterone; biochemical markers of inflammatory milieu; and validated questionnaires of nutrition, functional status, and QoL.
Results: The protocol opened to accrual in March 2017. To date, 12 patients have enrolled in study, and posttransplant evaluations (approximately 30 days after transplantation, median = 36) have been performed on 4. Early findings suggest relatively preserved body weight and composition but trends toward decreased QoL and fitness, particularly in aerobic capacity, handgrip strength, and total lower body fitness. Updated findings will be presented at the Association of VA Hematology/Oncology Conference.
Implications: With improving survival outcomes following HCT for hematologic malignancies due to advances in therapeutics and supportive care, increased attention will be directed at optimizing patient-centered quality outcomes. Understanding of the biochemical and physiologic factors underlying these outcomes may lead to refinements in prognostic models and present targets for risk mitigation interventions in the peri-transplant period.
Purpose: The objective of this study is to characterize biochemical and physiologic factors that contribute to changes in patient fitness, body composition, and quality of life (QoL) during hematopoietic stem cell transplantation (HCT).
Background: Though HCT can cure subsets of patients with hematologic malignancies, it carries a high risk of short- and long-term toxicity. Prior work has shown that following both autologous and allogeneic HCT, most patients suffer impairment in QoL for many months after transplant. Efforts to date have inconsistently demonstrated benefit in addressing parameters of nutrition, physical activity, and metabolism.
Methods: This prospective pilot study of 60 patients at VA Puget Sound Marrow Transplant Unit with hematologic malignancy will incorporate multidisciplinary evaluation by endocrinology, nutrition, gastroenterology, and oncology specialties. Assessments before and periodically after HCT include objective measures of fitness by 6-minue walk test, resting energy expenditure, maximum oxygen consumption, handgrip and other muscle group strength, and stair climbing power; body composition by bio-impedance and dual-energy X-ray absorptiometry scans; anabolic and catabolic factors such as insulin growth factor-1, growth hormone, and free and weakly bound testosterone; biochemical markers of inflammatory milieu; and validated questionnaires of nutrition, functional status, and QoL.
Results: The protocol opened to accrual in March 2017. To date, 12 patients have enrolled in study, and posttransplant evaluations (approximately 30 days after transplantation, median = 36) have been performed on 4. Early findings suggest relatively preserved body weight and composition but trends toward decreased QoL and fitness, particularly in aerobic capacity, handgrip strength, and total lower body fitness. Updated findings will be presented at the Association of VA Hematology/Oncology Conference.
Implications: With improving survival outcomes following HCT for hematologic malignancies due to advances in therapeutics and supportive care, increased attention will be directed at optimizing patient-centered quality outcomes. Understanding of the biochemical and physiologic factors underlying these outcomes may lead to refinements in prognostic models and present targets for risk mitigation interventions in the peri-transplant period.
Characterization of Hematology Consults for Complete Blood Count Abnormalities: A Single Center Experience in the Era of Electronic Consultation
Purpose: As patient volumes and complexity of hematology care increase, subspecialty provider efficiency is of utmost importance. We aim to improve efficiency by characterizing the nature and outcome of common hematology e-consults.
Background: Veterans Affairs Medical Centers pioneered electronic subspecialty consultation with the initiation of the e-consult system in 2011. An increase in number of hematology consultations at one VAMC from 391 in 2010 to 704 after e-consult implementation in 2013 was described by Cecchini et al (Blood, 2016).
Methods: A retrospective review of all hematology and oncology consults at one institution between April 1, 2016 and December 8, 2016 was performed. Cell counts, prior workup, diagnoses offered, age and comorbidities were determined for consults about complete blood count (CBC) abnormalities.
Results: 523 hematology/oncology consults were reviewed: 169 questioned CBC abnormalities, 76 consults were for anemia, and 38 consults were for thrombocytopenia. The most common diagnosis was iron-deficiency anemia (21.1% anemia consults). The most common hemoglobin value for anemia
consults was 9.0-9.9 g/dL (27.6% anemia consults). The most common platelet count for thrombocytopenia consults was 75k-100k (36.8% thrombocytopenia consults). Referring providers were significantly more likely to have initiated workup for anemia than for thrombocytopenia consults (71%
vs 29%, P < .0001). Consulting hematologists were significantly more likely to offer a diagnosis if basic workup had already been initiated (68% vs 39%, P = .0025). Age ≥ 70 years old had higher likelihood of 2-3 cell line abnormalities (RR 1.37, 95% CI, 1.02-1.82).
Conclusions: 169 consults about CBC abnormalities were reviewed. The most common reason for consult was anemia. Referring providers were significantly more likely to initiate a workup for anemia than for thrombocytopenia. There was a significantly greater likelihood of consultants offering a diagnosis if a basic workup had already been initiated. Increased education regarding mild anemia and basic workup of thrombocytopenia are areas of potential intervention to improve likelihood of diagnosis on initial consult and improve efficiency of the electronic consultation process.
Purpose: As patient volumes and complexity of hematology care increase, subspecialty provider efficiency is of utmost importance. We aim to improve efficiency by characterizing the nature and outcome of common hematology e-consults.
Background: Veterans Affairs Medical Centers pioneered electronic subspecialty consultation with the initiation of the e-consult system in 2011. An increase in number of hematology consultations at one VAMC from 391 in 2010 to 704 after e-consult implementation in 2013 was described by Cecchini et al (Blood, 2016).
Methods: A retrospective review of all hematology and oncology consults at one institution between April 1, 2016 and December 8, 2016 was performed. Cell counts, prior workup, diagnoses offered, age and comorbidities were determined for consults about complete blood count (CBC) abnormalities.
Results: 523 hematology/oncology consults were reviewed: 169 questioned CBC abnormalities, 76 consults were for anemia, and 38 consults were for thrombocytopenia. The most common diagnosis was iron-deficiency anemia (21.1% anemia consults). The most common hemoglobin value for anemia
consults was 9.0-9.9 g/dL (27.6% anemia consults). The most common platelet count for thrombocytopenia consults was 75k-100k (36.8% thrombocytopenia consults). Referring providers were significantly more likely to have initiated workup for anemia than for thrombocytopenia consults (71%
vs 29%, P < .0001). Consulting hematologists were significantly more likely to offer a diagnosis if basic workup had already been initiated (68% vs 39%, P = .0025). Age ≥ 70 years old had higher likelihood of 2-3 cell line abnormalities (RR 1.37, 95% CI, 1.02-1.82).
Conclusions: 169 consults about CBC abnormalities were reviewed. The most common reason for consult was anemia. Referring providers were significantly more likely to initiate a workup for anemia than for thrombocytopenia. There was a significantly greater likelihood of consultants offering a diagnosis if a basic workup had already been initiated. Increased education regarding mild anemia and basic workup of thrombocytopenia are areas of potential intervention to improve likelihood of diagnosis on initial consult and improve efficiency of the electronic consultation process.
Purpose: As patient volumes and complexity of hematology care increase, subspecialty provider efficiency is of utmost importance. We aim to improve efficiency by characterizing the nature and outcome of common hematology e-consults.
Background: Veterans Affairs Medical Centers pioneered electronic subspecialty consultation with the initiation of the e-consult system in 2011. An increase in number of hematology consultations at one VAMC from 391 in 2010 to 704 after e-consult implementation in 2013 was described by Cecchini et al (Blood, 2016).
Methods: A retrospective review of all hematology and oncology consults at one institution between April 1, 2016 and December 8, 2016 was performed. Cell counts, prior workup, diagnoses offered, age and comorbidities were determined for consults about complete blood count (CBC) abnormalities.
Results: 523 hematology/oncology consults were reviewed: 169 questioned CBC abnormalities, 76 consults were for anemia, and 38 consults were for thrombocytopenia. The most common diagnosis was iron-deficiency anemia (21.1% anemia consults). The most common hemoglobin value for anemia
consults was 9.0-9.9 g/dL (27.6% anemia consults). The most common platelet count for thrombocytopenia consults was 75k-100k (36.8% thrombocytopenia consults). Referring providers were significantly more likely to have initiated workup for anemia than for thrombocytopenia consults (71%
vs 29%, P < .0001). Consulting hematologists were significantly more likely to offer a diagnosis if basic workup had already been initiated (68% vs 39%, P = .0025). Age ≥ 70 years old had higher likelihood of 2-3 cell line abnormalities (RR 1.37, 95% CI, 1.02-1.82).
Conclusions: 169 consults about CBC abnormalities were reviewed. The most common reason for consult was anemia. Referring providers were significantly more likely to initiate a workup for anemia than for thrombocytopenia. There was a significantly greater likelihood of consultants offering a diagnosis if a basic workup had already been initiated. Increased education regarding mild anemia and basic workup of thrombocytopenia are areas of potential intervention to improve likelihood of diagnosis on initial consult and improve efficiency of the electronic consultation process.
Less lenalidomide may be more in frail elderly multiple myeloma patients
In frail elderly patients with multiple myeloma, starting lenalidomide at low doses was associated with fewer adverse events and less treatment discontinuation, and did not compromise overall response rates, in a single-center, retrospective study conducted in Japan.
Although most of the 56 study patients received 5-10 mg/day of lenalidomide, not the recommended 25-mg/day dose, their overall response rate was 73% (complete response in 17% of patients, very good partial response in 19%, and partial response in 37%), Aya Nakaya, MD, PhD, of Kansai Medical University, Hirakata, and colleagues wrote (Acta Haematol. 2017;138:55-60). In addition, 23% of patients had stable disease and 4% had disease progression. Nine patients developed other types of malignancies during treatment with lenalidomide.
Starting patients on a reduced dose and increasing it gradually while monitoring carefully for adverse events meant that patients did not have to stop treatment, the researchers said. Continuous treatment may improve survival, and “treatment with lenalidomide for long periods of time, even in small doses, may yield favorable outcomes.”
The 30 men and 26 women, mean age 76.5 years, were consecutively diagnosed as transplant-ineligible patients with relapsed/refractory multiple myeloma; 34%, 32%, and 34% had stages I-III disease, respectively. The M-protein consisted of IgG in 52% of patients and IgA in 30%, with Bence-Jones protein detected in 14%.
They were treated with lenalidomide plus dexamethasone at a starting dose determined by the treating physician; 73% were treated with lenalidomide as a second-line regimen and 14% as a third-line regimen. During each 28-day treatment cycle, patients received lenalidomide on days 1-21 and dexamethasone (20 or 40 mg) on days 1, 8, 15, and 22.
The most common starting lenalidomide dose was 10 mg/day (45%), followed by 5 mg/day (21%), 15 mg/day (20%), 20 mg/day (4%), and 25 mg/day (10%). The treatment dose used for the longest period was 10 mg/day (46% of patients), followed by 5 mg/day (25%), 15 mg/day (16%), 20 mg/day (4%), and 25 mg/day (9%).
The most frequent reasons for dose reduction were renal dysfunction (54%), fatigue (20%), hematologic disorder (14%), and rash (9%).
The median treatment period was 9 months (range 1-60 months) and the median follow-up period was 16 months.
The median time to disease progression was 11.8 months (range 8.4-21.9), and the median overall survival was 39.2 months. For those who took 5-10 mg of lenalidomide, the median time to progression was 14.5 months; for those who took lenalidomide at a dose of more than 10 mg, the median time to progression was 8.9 months. The median overall survival of the patients who received a 5- to 10-mg dose of lenalidomide was 38.9 months; the median overall survival of the patients given a dose of more than 10 mg was not available.
The authors declared no competing financial interests in relation to this work.
[email protected]
On Twitter @maryjodales
In frail elderly patients with multiple myeloma, starting lenalidomide at low doses was associated with fewer adverse events and less treatment discontinuation, and did not compromise overall response rates, in a single-center, retrospective study conducted in Japan.
Although most of the 56 study patients received 5-10 mg/day of lenalidomide, not the recommended 25-mg/day dose, their overall response rate was 73% (complete response in 17% of patients, very good partial response in 19%, and partial response in 37%), Aya Nakaya, MD, PhD, of Kansai Medical University, Hirakata, and colleagues wrote (Acta Haematol. 2017;138:55-60). In addition, 23% of patients had stable disease and 4% had disease progression. Nine patients developed other types of malignancies during treatment with lenalidomide.
Starting patients on a reduced dose and increasing it gradually while monitoring carefully for adverse events meant that patients did not have to stop treatment, the researchers said. Continuous treatment may improve survival, and “treatment with lenalidomide for long periods of time, even in small doses, may yield favorable outcomes.”
The 30 men and 26 women, mean age 76.5 years, were consecutively diagnosed as transplant-ineligible patients with relapsed/refractory multiple myeloma; 34%, 32%, and 34% had stages I-III disease, respectively. The M-protein consisted of IgG in 52% of patients and IgA in 30%, with Bence-Jones protein detected in 14%.
They were treated with lenalidomide plus dexamethasone at a starting dose determined by the treating physician; 73% were treated with lenalidomide as a second-line regimen and 14% as a third-line regimen. During each 28-day treatment cycle, patients received lenalidomide on days 1-21 and dexamethasone (20 or 40 mg) on days 1, 8, 15, and 22.
The most common starting lenalidomide dose was 10 mg/day (45%), followed by 5 mg/day (21%), 15 mg/day (20%), 20 mg/day (4%), and 25 mg/day (10%). The treatment dose used for the longest period was 10 mg/day (46% of patients), followed by 5 mg/day (25%), 15 mg/day (16%), 20 mg/day (4%), and 25 mg/day (9%).
The most frequent reasons for dose reduction were renal dysfunction (54%), fatigue (20%), hematologic disorder (14%), and rash (9%).
The median treatment period was 9 months (range 1-60 months) and the median follow-up period was 16 months.
The median time to disease progression was 11.8 months (range 8.4-21.9), and the median overall survival was 39.2 months. For those who took 5-10 mg of lenalidomide, the median time to progression was 14.5 months; for those who took lenalidomide at a dose of more than 10 mg, the median time to progression was 8.9 months. The median overall survival of the patients who received a 5- to 10-mg dose of lenalidomide was 38.9 months; the median overall survival of the patients given a dose of more than 10 mg was not available.
The authors declared no competing financial interests in relation to this work.
[email protected]
On Twitter @maryjodales
In frail elderly patients with multiple myeloma, starting lenalidomide at low doses was associated with fewer adverse events and less treatment discontinuation, and did not compromise overall response rates, in a single-center, retrospective study conducted in Japan.
Although most of the 56 study patients received 5-10 mg/day of lenalidomide, not the recommended 25-mg/day dose, their overall response rate was 73% (complete response in 17% of patients, very good partial response in 19%, and partial response in 37%), Aya Nakaya, MD, PhD, of Kansai Medical University, Hirakata, and colleagues wrote (Acta Haematol. 2017;138:55-60). In addition, 23% of patients had stable disease and 4% had disease progression. Nine patients developed other types of malignancies during treatment with lenalidomide.
Starting patients on a reduced dose and increasing it gradually while monitoring carefully for adverse events meant that patients did not have to stop treatment, the researchers said. Continuous treatment may improve survival, and “treatment with lenalidomide for long periods of time, even in small doses, may yield favorable outcomes.”
The 30 men and 26 women, mean age 76.5 years, were consecutively diagnosed as transplant-ineligible patients with relapsed/refractory multiple myeloma; 34%, 32%, and 34% had stages I-III disease, respectively. The M-protein consisted of IgG in 52% of patients and IgA in 30%, with Bence-Jones protein detected in 14%.
They were treated with lenalidomide plus dexamethasone at a starting dose determined by the treating physician; 73% were treated with lenalidomide as a second-line regimen and 14% as a third-line regimen. During each 28-day treatment cycle, patients received lenalidomide on days 1-21 and dexamethasone (20 or 40 mg) on days 1, 8, 15, and 22.
The most common starting lenalidomide dose was 10 mg/day (45%), followed by 5 mg/day (21%), 15 mg/day (20%), 20 mg/day (4%), and 25 mg/day (10%). The treatment dose used for the longest period was 10 mg/day (46% of patients), followed by 5 mg/day (25%), 15 mg/day (16%), 20 mg/day (4%), and 25 mg/day (9%).
The most frequent reasons for dose reduction were renal dysfunction (54%), fatigue (20%), hematologic disorder (14%), and rash (9%).
The median treatment period was 9 months (range 1-60 months) and the median follow-up period was 16 months.
The median time to disease progression was 11.8 months (range 8.4-21.9), and the median overall survival was 39.2 months. For those who took 5-10 mg of lenalidomide, the median time to progression was 14.5 months; for those who took lenalidomide at a dose of more than 10 mg, the median time to progression was 8.9 months. The median overall survival of the patients who received a 5- to 10-mg dose of lenalidomide was 38.9 months; the median overall survival of the patients given a dose of more than 10 mg was not available.
The authors declared no competing financial interests in relation to this work.
[email protected]
On Twitter @maryjodales
FROM ACTA HAEMATOLOGICA
Key clinical point:
Major finding: Although most of the 56 study patients received 5-10 mg/day of lenalidomide, not the recommended 25-mg/day dose, their overall response rate was 73%.
Data source: A single-center, retrospective study of 56 consecutively diagnosed transplant-ineligible patients in Japan.
Disclosures: The authors declared no competing financial interests in relation to this work.
Four drugs better than three for myeloma induction
MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.
In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.
In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.
“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.
Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.
For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.
They chose carfilzomib as the proteasome-inhibitor backbone of the quadruplet because of its selective, irreversible target binding, lower incidence of peripheral neuropathy (compared with bortezomib), and efficacy in both the frontline and relapsed/refractory setting, she said.
Asked why the comparator regimens did not contain a proteasome inhibitor, Dr. Pawlyn said that while the current standard for induction therapy in the United Kingdom is bortezomib, thalidomide, and dexamethasone, CTD was the standard of care at the time of study planning and initial enrollment.
The trial was open to all patients in the United Kingdom of all ages with newly diagnosed symptomatic multiple myeloma, with pathways for both transplant-eligible and transplant-ineligible patients. The only main exclusion criteria were for patients with dialysis-dependent renal failure and for those who had a prior or concurrent malignancy.
A total of 1,021 patients were assigned to each of the CTD and CRD cohorts, and 526 patients were assigned to the KCRD cohort. The cohorts were well balanced by sex, age, World Health Organization performance score, and other parameters.
Patients randomized to either CTD or CRD were assessed for response after a minimum of four induction cycles, with treatment continued until best response. Those with a VGPR or better went on to ASCT, while those with a partial response were randomized to either a second induction with cyclophosphamide, bortezomib, and dexamethasone (CVD) or no CVD, and then proceeded to transplant. Patients with stable disease or disease progression in either of these arms went on to CVD prior to ASCT.
In the KCRD arm, all patients went from induction to transplant. Following ASCT, patients were randomized to either observation or lenalidomide maintenance.
A higher proportion of patients assigned to KCRD completed the minimum of four induction cycles, and few patients in any trial arm had to stop induction therapy because of adverse events. Dose modifications were required in 63.9% of patients on KCRD, 56.3% of patients on CRD, and 82.2% of patients on CTD.
There was no significant cardiac signal seen in the study, and no difference in the incidence of venous thromboembolic events among the treatment arms.
As noted before, rates of VGPR or better after initial induction were highest in the KCRD arm, at 79.5%, compared with 60% for CRD, and 52.8% for CTD.
“The KCRD quadruplet achieved the highest speed and depth of response,” Dr. Pawlyn said.
The pattern of responses was similar across all cytogenetic risk groups, she added.
A higher proportion of patients treated with KCRD went on to ASCT, and the pattern of deeper responses among patients who underwent induction with KCRD persisted, with 92.1% of patients having a post-transplant VGPR or better, compared with 81.8% for CRD and 77.0% for CTD (statistical significance not shown).
Again, the pattern of responses post-transplant was similar across cytogenetic risk groups.
The investigators anticipate receiving PFS results from the Myeloma XI study in the third or fourth quarter of 2017.
The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.
In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.
In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.
“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.
Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.
For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.
They chose carfilzomib as the proteasome-inhibitor backbone of the quadruplet because of its selective, irreversible target binding, lower incidence of peripheral neuropathy (compared with bortezomib), and efficacy in both the frontline and relapsed/refractory setting, she said.
Asked why the comparator regimens did not contain a proteasome inhibitor, Dr. Pawlyn said that while the current standard for induction therapy in the United Kingdom is bortezomib, thalidomide, and dexamethasone, CTD was the standard of care at the time of study planning and initial enrollment.
The trial was open to all patients in the United Kingdom of all ages with newly diagnosed symptomatic multiple myeloma, with pathways for both transplant-eligible and transplant-ineligible patients. The only main exclusion criteria were for patients with dialysis-dependent renal failure and for those who had a prior or concurrent malignancy.
A total of 1,021 patients were assigned to each of the CTD and CRD cohorts, and 526 patients were assigned to the KCRD cohort. The cohorts were well balanced by sex, age, World Health Organization performance score, and other parameters.
Patients randomized to either CTD or CRD were assessed for response after a minimum of four induction cycles, with treatment continued until best response. Those with a VGPR or better went on to ASCT, while those with a partial response were randomized to either a second induction with cyclophosphamide, bortezomib, and dexamethasone (CVD) or no CVD, and then proceeded to transplant. Patients with stable disease or disease progression in either of these arms went on to CVD prior to ASCT.
In the KCRD arm, all patients went from induction to transplant. Following ASCT, patients were randomized to either observation or lenalidomide maintenance.
A higher proportion of patients assigned to KCRD completed the minimum of four induction cycles, and few patients in any trial arm had to stop induction therapy because of adverse events. Dose modifications were required in 63.9% of patients on KCRD, 56.3% of patients on CRD, and 82.2% of patients on CTD.
There was no significant cardiac signal seen in the study, and no difference in the incidence of venous thromboembolic events among the treatment arms.
As noted before, rates of VGPR or better after initial induction were highest in the KCRD arm, at 79.5%, compared with 60% for CRD, and 52.8% for CTD.
“The KCRD quadruplet achieved the highest speed and depth of response,” Dr. Pawlyn said.
The pattern of responses was similar across all cytogenetic risk groups, she added.
A higher proportion of patients treated with KCRD went on to ASCT, and the pattern of deeper responses among patients who underwent induction with KCRD persisted, with 92.1% of patients having a post-transplant VGPR or better, compared with 81.8% for CRD and 77.0% for CTD (statistical significance not shown).
Again, the pattern of responses post-transplant was similar across cytogenetic risk groups.
The investigators anticipate receiving PFS results from the Myeloma XI study in the third or fourth quarter of 2017.
The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.
In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.
In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.
“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.
Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.
For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.
They chose carfilzomib as the proteasome-inhibitor backbone of the quadruplet because of its selective, irreversible target binding, lower incidence of peripheral neuropathy (compared with bortezomib), and efficacy in both the frontline and relapsed/refractory setting, she said.
Asked why the comparator regimens did not contain a proteasome inhibitor, Dr. Pawlyn said that while the current standard for induction therapy in the United Kingdom is bortezomib, thalidomide, and dexamethasone, CTD was the standard of care at the time of study planning and initial enrollment.
The trial was open to all patients in the United Kingdom of all ages with newly diagnosed symptomatic multiple myeloma, with pathways for both transplant-eligible and transplant-ineligible patients. The only main exclusion criteria were for patients with dialysis-dependent renal failure and for those who had a prior or concurrent malignancy.
A total of 1,021 patients were assigned to each of the CTD and CRD cohorts, and 526 patients were assigned to the KCRD cohort. The cohorts were well balanced by sex, age, World Health Organization performance score, and other parameters.
Patients randomized to either CTD or CRD were assessed for response after a minimum of four induction cycles, with treatment continued until best response. Those with a VGPR or better went on to ASCT, while those with a partial response were randomized to either a second induction with cyclophosphamide, bortezomib, and dexamethasone (CVD) or no CVD, and then proceeded to transplant. Patients with stable disease or disease progression in either of these arms went on to CVD prior to ASCT.
In the KCRD arm, all patients went from induction to transplant. Following ASCT, patients were randomized to either observation or lenalidomide maintenance.
A higher proportion of patients assigned to KCRD completed the minimum of four induction cycles, and few patients in any trial arm had to stop induction therapy because of adverse events. Dose modifications were required in 63.9% of patients on KCRD, 56.3% of patients on CRD, and 82.2% of patients on CTD.
There was no significant cardiac signal seen in the study, and no difference in the incidence of venous thromboembolic events among the treatment arms.
As noted before, rates of VGPR or better after initial induction were highest in the KCRD arm, at 79.5%, compared with 60% for CRD, and 52.8% for CTD.
“The KCRD quadruplet achieved the highest speed and depth of response,” Dr. Pawlyn said.
The pattern of responses was similar across all cytogenetic risk groups, she added.
A higher proportion of patients treated with KCRD went on to ASCT, and the pattern of deeper responses among patients who underwent induction with KCRD persisted, with 92.1% of patients having a post-transplant VGPR or better, compared with 81.8% for CRD and 77.0% for CTD (statistical significance not shown).
Again, the pattern of responses post-transplant was similar across cytogenetic risk groups.
The investigators anticipate receiving PFS results from the Myeloma XI study in the third or fourth quarter of 2017.
The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
AT THE EHA CONGRESS
Key clinical point:
Major finding: An induction quadruplet containing carfilzomib induced a higher rate of very good partial responses or better vs. regimens without a proteasome inhibitor.
Data source: A randomized, open-label, parallel group study of 2,568 patients with newly diagnosed multiple myeloma.
Disclosures: The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
Avelumab induces response in Hodgkin lymphoma after failed allo-SCT
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
AT 14-ICML
Key clinical point: Avelumab showed efficacy in patients with classical Hodgkin lymphoma that relapsed following allogeneic stem cell transplant.
Major finding: The objective response rate among all patients in the study was 41.9%.
Data source: A phase 1 dose-finding and expansion study in 31 patients with relapsed/refractory classical Hodgkin lymphoma who were ineligible for SCT or experienced relapses following SCT.
Disclosures: The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
A New ‘Triplet’ Treatment for Multiple Myeloma
Carfilzomib, a selective second-generation proteasome inhibitor, has performed well in clinical trials. So because other “triplets”—combinations of alkylator, proteasome inhibitor, and steroid—had shown “encouraging” response rates, researchers from the Center for Cancer and Blood Disorders in Bethesda, Maryland, and others, conducted a multicenter study to evaluate the safety and tolerability of twice-weekly carfilzomib combined with cyclophosphamide and dexamethasone (KCyd) for patients newly diagnosed with multiple myeloma (MM).
The researchers tested 3 doses of carfilzomib: 36 mg/m2, 45 mg/m2, and 56 mg/m2. Of the 22 enrolled patients, 16 were treated with the maximum dose.
Fourteen patients completed all 8 cycles of treatment; 10 in the maximum-dose group completed all 8. At 56 mg/m2, the overall response rate was 87.5%. Among the 14 patients whose disease responded to therapy, the median time to response was 1 month.
Five patients discontinued treatment because of adverse effects (AEs), but the researchers found no dose-limiting toxicities at any of the dose levels. The most common AEs were nausea, diarrhea, and anemia.
The researchers concluded that based on previous research, KCyd with 36 mg/m2 is safe and effective in patients aged ≥ 65 years with newly diagnosed MM. However, their findings suggest that twice-weekly carfilzomib 56 mg/m2 in combination with cyclophosphamide and dexamethasone also is effective with “manageable toxicity.”
Source:
Boccia RV, Bessudo A, Agajanian R, et al. Clin Lymphoma Myeloma Leuk. In press.
doi: 10.1016/j.clml.2017.05.009.
Carfilzomib, a selective second-generation proteasome inhibitor, has performed well in clinical trials. So because other “triplets”—combinations of alkylator, proteasome inhibitor, and steroid—had shown “encouraging” response rates, researchers from the Center for Cancer and Blood Disorders in Bethesda, Maryland, and others, conducted a multicenter study to evaluate the safety and tolerability of twice-weekly carfilzomib combined with cyclophosphamide and dexamethasone (KCyd) for patients newly diagnosed with multiple myeloma (MM).
The researchers tested 3 doses of carfilzomib: 36 mg/m2, 45 mg/m2, and 56 mg/m2. Of the 22 enrolled patients, 16 were treated with the maximum dose.
Fourteen patients completed all 8 cycles of treatment; 10 in the maximum-dose group completed all 8. At 56 mg/m2, the overall response rate was 87.5%. Among the 14 patients whose disease responded to therapy, the median time to response was 1 month.
Five patients discontinued treatment because of adverse effects (AEs), but the researchers found no dose-limiting toxicities at any of the dose levels. The most common AEs were nausea, diarrhea, and anemia.
The researchers concluded that based on previous research, KCyd with 36 mg/m2 is safe and effective in patients aged ≥ 65 years with newly diagnosed MM. However, their findings suggest that twice-weekly carfilzomib 56 mg/m2 in combination with cyclophosphamide and dexamethasone also is effective with “manageable toxicity.”
Source:
Boccia RV, Bessudo A, Agajanian R, et al. Clin Lymphoma Myeloma Leuk. In press.
doi: 10.1016/j.clml.2017.05.009.
Carfilzomib, a selective second-generation proteasome inhibitor, has performed well in clinical trials. So because other “triplets”—combinations of alkylator, proteasome inhibitor, and steroid—had shown “encouraging” response rates, researchers from the Center for Cancer and Blood Disorders in Bethesda, Maryland, and others, conducted a multicenter study to evaluate the safety and tolerability of twice-weekly carfilzomib combined with cyclophosphamide and dexamethasone (KCyd) for patients newly diagnosed with multiple myeloma (MM).
The researchers tested 3 doses of carfilzomib: 36 mg/m2, 45 mg/m2, and 56 mg/m2. Of the 22 enrolled patients, 16 were treated with the maximum dose.
Fourteen patients completed all 8 cycles of treatment; 10 in the maximum-dose group completed all 8. At 56 mg/m2, the overall response rate was 87.5%. Among the 14 patients whose disease responded to therapy, the median time to response was 1 month.
Five patients discontinued treatment because of adverse effects (AEs), but the researchers found no dose-limiting toxicities at any of the dose levels. The most common AEs were nausea, diarrhea, and anemia.
The researchers concluded that based on previous research, KCyd with 36 mg/m2 is safe and effective in patients aged ≥ 65 years with newly diagnosed MM. However, their findings suggest that twice-weekly carfilzomib 56 mg/m2 in combination with cyclophosphamide and dexamethasone also is effective with “manageable toxicity.”
Source:
Boccia RV, Bessudo A, Agajanian R, et al. Clin Lymphoma Myeloma Leuk. In press.
doi: 10.1016/j.clml.2017.05.009.
Atypical Femoral Fracture Due to Daily Ibandronate
As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.
The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.
While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.
Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.
Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.
Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.
Source:
Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.
As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.
The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.
While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.
Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.
Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.
Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.
Source:
Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.
As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.
The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.
While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.
Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.
Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.
Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.
Source:
Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.
Infections may trigger leukemia in the genetically susceptible
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
AT EHA 2017
Key clinical point: This study suggests a link between acute lymphocytic leukemia development and infections in some genetically predisposed children.
Major finding: Mouse models of two types of B-cell precursor ALL developed leukemia only after exposure to infections.
Data source: A study of factors related to the development of childhood ALL using genetically modified mouse models.
Disclosures: The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
Chemo-free induction in MCL keeps getting better
Lugano, Switzerland – It’s not the end of chemotherapy for young patients with newly diagnosed mantle cell lymphoma (MCL), but it’s a start.
For these patients, induction with a combination of ibrutinib and rituximab, followed by shorter cycles of chemoimmunotherapy, was associated in an early study with an objective response rate of 100%, including 90% complete responses (CR), reported Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This is the first time for a chemo-free therapy – ibrutinib/rituximab – to achieve an overall response rate of 100%. This has an unprecedented efficacy in the frontline in young patients with mantle-cell lymphoma,” he said at the 14th International Congress on Malignant Lymphoma.
In patients with relapsed or refractory MCL, the combination of ibrutinib and rituximab has been associated with durable responses in 88% of patients. The success of the combination suggests that fit patients younger than age 65 years with newly diagnosed MCL might benefit from a chemotherapy-free induction regimen with ibrutinib and rituximab, followed by consolidation with a short but intense course of chemoimmunotherapy, Dr. Wang said.
He presented updated results from the phase II Window I study, first results of which were reported at the 2016 meeting of the American Society of Hematology.
“Frontline therapy is the most important therapy for mantle cell lymphoma, because mantle cell lymphoma cells are most vulnerable to frontline attack. If the frontline therapy is good enough, it could kill all the mantle cell lymphoma cells, therefore leaving no chance for secondary resistance, and thereby (resulting in) long-term survival. And it is really my belief that if we ideally optimized the frontline therapy, that would be a shortcut to a cure,” he said.
To test this idea, Dr. Wang and MD Anderson colleagues initiated a phase II trial at their institution with 50 patients age 65 years or under with newly diagnosed, CD20-positive and Cyclin D1-positive MCL.
A total of 50 patients age 65 years or younger (median age 54) with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib 560 mg, plus rituximab 375 mg/m2 administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating every 28 days with rituximab plus high-dose methotrexate–cytarabine.
Patients who had complete responses to induction received four cycles of chemoimmunotherapy, while those who experienced disease progression and those who had partial responses received chemoimmunotherapy for two cycles beyond the point of complete remissions.
At the time of the presentation, all 50 patients were evaluable for the induction phase (part 2), and 47 were evaluable for both induction and consolidation (part 2) .Of the evaluable patients, the overall response rate (ORR) to chemotherapy-free induction therapy alone (Part 1 ) was 100% (50), with CR in 90% of patients and partial responses (PR) in 10%. Of the 47 patients evaluable for part 2 (chemoimmunotherapy), all had CRs, for an ORR of 100%.
Dr. Wang noted that one patient had a dramatic radiographic reduction in spleen size following just two cycles of chemotherapy-free induction, and two other patients had similar reductions after four and six cycles, respectively.
After a median follow-up of 15.9 months, neither the median duration of response, progression-free survival, nor overall survival have been reached. There have been no deaths and only one case of disease progression after one year of therapy.
The patients generally tolerated the regimen very well, Dr. Wang said. There were no cases of lymphocytosis, bleeding, or atrial fibrillation after 332 combined cycles.
Nonhematological adverse events were primarily grade 1 or 2. Grade 3 fatigue was reported in approximately 10% of patients. There were no grade 4 adverse events.
“This study may provide a window of opportunity to reduce the frontline therapies and reduce the long-term toxicities such as secondary malignancies.” Dr. Wang said.
He acknowledged that four cycles of intensive chemotherapy is still toxic and that further efforts to reduce these toxicities are needed. The investigators are currently planning the Window II study, in which a fraction of patients will be treated with no chemotherapy at all, he said.
The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
Lugano, Switzerland – It’s not the end of chemotherapy for young patients with newly diagnosed mantle cell lymphoma (MCL), but it’s a start.
For these patients, induction with a combination of ibrutinib and rituximab, followed by shorter cycles of chemoimmunotherapy, was associated in an early study with an objective response rate of 100%, including 90% complete responses (CR), reported Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This is the first time for a chemo-free therapy – ibrutinib/rituximab – to achieve an overall response rate of 100%. This has an unprecedented efficacy in the frontline in young patients with mantle-cell lymphoma,” he said at the 14th International Congress on Malignant Lymphoma.
In patients with relapsed or refractory MCL, the combination of ibrutinib and rituximab has been associated with durable responses in 88% of patients. The success of the combination suggests that fit patients younger than age 65 years with newly diagnosed MCL might benefit from a chemotherapy-free induction regimen with ibrutinib and rituximab, followed by consolidation with a short but intense course of chemoimmunotherapy, Dr. Wang said.
He presented updated results from the phase II Window I study, first results of which were reported at the 2016 meeting of the American Society of Hematology.
“Frontline therapy is the most important therapy for mantle cell lymphoma, because mantle cell lymphoma cells are most vulnerable to frontline attack. If the frontline therapy is good enough, it could kill all the mantle cell lymphoma cells, therefore leaving no chance for secondary resistance, and thereby (resulting in) long-term survival. And it is really my belief that if we ideally optimized the frontline therapy, that would be a shortcut to a cure,” he said.
To test this idea, Dr. Wang and MD Anderson colleagues initiated a phase II trial at their institution with 50 patients age 65 years or under with newly diagnosed, CD20-positive and Cyclin D1-positive MCL.
A total of 50 patients age 65 years or younger (median age 54) with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib 560 mg, plus rituximab 375 mg/m2 administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating every 28 days with rituximab plus high-dose methotrexate–cytarabine.
Patients who had complete responses to induction received four cycles of chemoimmunotherapy, while those who experienced disease progression and those who had partial responses received chemoimmunotherapy for two cycles beyond the point of complete remissions.
At the time of the presentation, all 50 patients were evaluable for the induction phase (part 2), and 47 were evaluable for both induction and consolidation (part 2) .Of the evaluable patients, the overall response rate (ORR) to chemotherapy-free induction therapy alone (Part 1 ) was 100% (50), with CR in 90% of patients and partial responses (PR) in 10%. Of the 47 patients evaluable for part 2 (chemoimmunotherapy), all had CRs, for an ORR of 100%.
Dr. Wang noted that one patient had a dramatic radiographic reduction in spleen size following just two cycles of chemotherapy-free induction, and two other patients had similar reductions after four and six cycles, respectively.
After a median follow-up of 15.9 months, neither the median duration of response, progression-free survival, nor overall survival have been reached. There have been no deaths and only one case of disease progression after one year of therapy.
The patients generally tolerated the regimen very well, Dr. Wang said. There were no cases of lymphocytosis, bleeding, or atrial fibrillation after 332 combined cycles.
Nonhematological adverse events were primarily grade 1 or 2. Grade 3 fatigue was reported in approximately 10% of patients. There were no grade 4 adverse events.
“This study may provide a window of opportunity to reduce the frontline therapies and reduce the long-term toxicities such as secondary malignancies.” Dr. Wang said.
He acknowledged that four cycles of intensive chemotherapy is still toxic and that further efforts to reduce these toxicities are needed. The investigators are currently planning the Window II study, in which a fraction of patients will be treated with no chemotherapy at all, he said.
The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
Lugano, Switzerland – It’s not the end of chemotherapy for young patients with newly diagnosed mantle cell lymphoma (MCL), but it’s a start.
For these patients, induction with a combination of ibrutinib and rituximab, followed by shorter cycles of chemoimmunotherapy, was associated in an early study with an objective response rate of 100%, including 90% complete responses (CR), reported Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This is the first time for a chemo-free therapy – ibrutinib/rituximab – to achieve an overall response rate of 100%. This has an unprecedented efficacy in the frontline in young patients with mantle-cell lymphoma,” he said at the 14th International Congress on Malignant Lymphoma.
In patients with relapsed or refractory MCL, the combination of ibrutinib and rituximab has been associated with durable responses in 88% of patients. The success of the combination suggests that fit patients younger than age 65 years with newly diagnosed MCL might benefit from a chemotherapy-free induction regimen with ibrutinib and rituximab, followed by consolidation with a short but intense course of chemoimmunotherapy, Dr. Wang said.
He presented updated results from the phase II Window I study, first results of which were reported at the 2016 meeting of the American Society of Hematology.
“Frontline therapy is the most important therapy for mantle cell lymphoma, because mantle cell lymphoma cells are most vulnerable to frontline attack. If the frontline therapy is good enough, it could kill all the mantle cell lymphoma cells, therefore leaving no chance for secondary resistance, and thereby (resulting in) long-term survival. And it is really my belief that if we ideally optimized the frontline therapy, that would be a shortcut to a cure,” he said.
To test this idea, Dr. Wang and MD Anderson colleagues initiated a phase II trial at their institution with 50 patients age 65 years or under with newly diagnosed, CD20-positive and Cyclin D1-positive MCL.
A total of 50 patients age 65 years or younger (median age 54) with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib 560 mg, plus rituximab 375 mg/m2 administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating every 28 days with rituximab plus high-dose methotrexate–cytarabine.
Patients who had complete responses to induction received four cycles of chemoimmunotherapy, while those who experienced disease progression and those who had partial responses received chemoimmunotherapy for two cycles beyond the point of complete remissions.
At the time of the presentation, all 50 patients were evaluable for the induction phase (part 2), and 47 were evaluable for both induction and consolidation (part 2) .Of the evaluable patients, the overall response rate (ORR) to chemotherapy-free induction therapy alone (Part 1 ) was 100% (50), with CR in 90% of patients and partial responses (PR) in 10%. Of the 47 patients evaluable for part 2 (chemoimmunotherapy), all had CRs, for an ORR of 100%.
Dr. Wang noted that one patient had a dramatic radiographic reduction in spleen size following just two cycles of chemotherapy-free induction, and two other patients had similar reductions after four and six cycles, respectively.
After a median follow-up of 15.9 months, neither the median duration of response, progression-free survival, nor overall survival have been reached. There have been no deaths and only one case of disease progression after one year of therapy.
The patients generally tolerated the regimen very well, Dr. Wang said. There were no cases of lymphocytosis, bleeding, or atrial fibrillation after 332 combined cycles.
Nonhematological adverse events were primarily grade 1 or 2. Grade 3 fatigue was reported in approximately 10% of patients. There were no grade 4 adverse events.
“This study may provide a window of opportunity to reduce the frontline therapies and reduce the long-term toxicities such as secondary malignancies.” Dr. Wang said.
He acknowledged that four cycles of intensive chemotherapy is still toxic and that further efforts to reduce these toxicities are needed. The investigators are currently planning the Window II study, in which a fraction of patients will be treated with no chemotherapy at all, he said.
The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
AT14-ICML
Key clinical point: A chemotherapy-free induction regimen with ibrutinib and rituximab was associated with high response rates in patients with newly diagnosed mantle cell lymphoma (MCL).
Major finding: The overall response rate after induction was 100%, including 90% complete responses.
Data source: Update results from phase II investigator-initiated study in 50 patients aged 65 years and younger with MCL.
Disclosures: The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
Sequential triple therapy produces high response rates in CLL
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
AT 14-ICML
Key clinical point: Sequential therapy with bendamustine, obinutuzumab, and venetoclax was associated with high response rates in patients with both treatment-naive and relapsed/refractory chronic lymphocytic leukemia.
Major finding: The overall response rate at the end of induction was 95%.
Data source: An open-label prospective study in 66 patients with CLL.
Disclosures: The study was sponsored by the German CLL study group. Dr. Cramer and her coauthors disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.