Healing after rotator cuff repair (RCR) can be challenging, especially in cases of large and massive tears, revision repairs, and tendons with poor tissue quality.^1-3 Poor tissue quality is associated with increased risk for recurrent tears, independent of age and tear size.³ Various techniques have been used to improve tendon fixation strength in these difficult situations, including augmented suture configurations (eg, massive cuff stitches, rip-stop stitches) and tissue grafts (eg, acellular dermal matrix).^4-9 Clinical studies have found improved healing rates for larger tears and revision repairs using acellular dermal matrix grafts.^6,10 Synthetic patches are another option for RCR augmentation, but limited clinical data and biomechanical evidence support use of synthetic grafts as an augment for RCRs.^11-13

Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers that have been used as orthopedic devices, tissue scaffolds, patches, and other applications with increasing frequency over the past decade.¹⁴ In the laboratory, these implanted materials have been shown to support cell migration and growth.¹⁵ The PHA family of polymers typically degrades by hydrolytic and bacterial depolymerase mechanisms over 52-plus weeks in vivo.¹⁴PHA grafts have been studied in the setting of RCR. An expanded polytetrafluoroethylene scaffold was shown to improve repair mechanics when used as a bursal side graft in an in vitro ovine model.¹¹ The graft increased tendon footprint contact pressure and failure loads by almost 180 N. In clinical studies, poly-L-lactic acid augmentations have been used to reinforce massive RCRs. Lenart and colleagues¹⁶ found that 38% of 16 patients with such tears had an intact rotator cuff at 1.2-year follow-up, and improvement in clinical scores. Proctor¹³ reported on use of a poly-L-lactic acid retrograde patch for reinforcement of massive tears with both single- and double-row repairs in 18 patients. The cohort had more favorable rates of intact cuffs at 12 months (83%) and 42 months (78%), and ASES (American Shoulder and Elbow Surgeons) scores improved from 25 before surgery to 82 at latest follow-up after surgery.

RCR augmentation traditionally has been performed with an open or mini-open technique.⁶ Recently, several authors have reported on arthroscopic techniques for augmentation with either acellular dermal matrix or synthetic grafts.^13,17,18 Most techniques have involved “bridging” with a graft or patch used to stress-shield a single-row repair.^8,9,13 This bridging typically involves placing several sutures medial to where the anchor repair stitches pass through the tendon. An alternative is to pass the repair stitches through both the tendon and the graft.^17-19 The overall volume of tissue incorporated into the repair stitches (rotator cuff plus graft) is increased with the augmented technique relative to the bridging technique. Both can be technically challenging, but the augmented technique may be easier to perform arthroscopically.^9,19 Regardless, these techniques are complicated and require a higher level of arthroscopic skills compared with those required in arthroscopic RCR without a graft. Simplifying arthroscopic graft augmentation likely will increase its utility because, even for skilled surgeons, adding a graft can increase operative time by 20 to 30 minutes. Simplification will also extend use of the technique to surgeons with less experience and proficiency with arthroscopic repair.

We developed a simple method for augmenting single-row RCR with a strip of bioresorbable soft-tissue scaffold. We also conducted a study to evaluate the initial biomechanical properties of single-row RCR in cadaveric shoulder specimens augmented with PHA mesh (BioFiber; Tornier) graft as compared with single-row RCR without augmentation. Both cyclic gap formation and ultimate failure loads and displacement were quantified. We hypothesized that the augmented RCRs would have decreased gap formation and increased ultimate failure loads compared with nonaugmented RCRs. This study was exempt from having to obtain Institutional Review Board approval.

Methods

Eight pairs of fresh-frozen cadaver humeri (6 male, 2 female; mean [SD] age, 61 [9] years) were dissected of all soft tissue (except rotator cuff) by Dr. Tashjian, a board-certified, fellowship-trained orthopedic surgeon. There were no qualitative differences in tendon condition between tendons within a pair. The supraspinatus muscle and tendon were separated from the other rotator cuff muscles. The infraspinatus, subscapularis, and teres minor were removed from the humerus. Last, the supraspinatus was resected at its insertion. Humeral pairs were then randomized into augmented and nonaugmented RCRs within each pair.

In the nonaugmented group, the supraspinatus was reattached to its insertion in a single-row RCR with 2 triple-loaded suture anchors (5.5-mm Insite FT Ti, No. 2 Force Fiber suture; Tornier) and 6 simple stitches (Figure 1A). Anchors were placed midway between the articular margin and the lateral edge of the greater tuberosity at about 45° to the bone surface.

21

Statistical Analysis

Paired t tests were used to compare the matched pairs of constructs. For all tests, significance was set at P ≤ .05. Post hoc power was calculated for significant results using G*Power Version 3.1.6.²³ All data are presented as means (SDs).

Results

After 1000 cycles of displacement, mean (SD) gapping was 3.8 (0.9) mm for the nonaugmented repairs and 3.9 (1.1) mm for the PHA mesh–augmented repairs (P = .879) (Figure 4).

For the nonaugmented repairs, mean (SD) failure displacement was 6.3 (1.7) mm, and mean (SD) ultimate failure load was 472.1 (120.3) N. For the PHA-augmented repairs, failure displacement was 5.5 (1.9) mm, and ultimate failure load was 571.2 (173.0) N. There was no difference in failure displacement (P = .393), but there was a difference in ultimate failure load (P = .042; power = 0.57). During failure testing, mean (SD) tissue deformation was higher (P = .012; power = 0.83) for the PHA-augmented repairs, 1.2 (0.7) mm, than for the nonaugmented repairs, 0.8 (0.5) mm. Failures, which were consistent within pairs, were caused by tissue failure, with sutures pulling through the tissue (4 pairs) or single anchor pullout before ultimate tissue failure (4 pairs). Of the 4 failures with anchor pullout, 3 had anterior anchor pullout, and 1 had posterior anchor pullout. In all specimens with anchor pullout, the second anchor remained stable, and ultimate failure occurred with tissue tearing at the suture interface. There were no significant differences in any metrics between specimens that failed with intact anchors and specimens with single anchor pullout (P ≥ .122). Therefore, both groups were pooled for the failure analysis.

Discussion

RCR augmentation with a synthetic graft is a viable option for improving fixation strength of supraspinatus repairs, as shown in otherwise healthy tendon in the present study. Our hypothesis that there would be decreased gap formation with graft augmentation was not supported, whereas the hypothesis of increased failure loads with graft augmentation was supported. These findings may also be applicable in cases of large tears, revisions, and tendons with poor tissue quality. Simplification of graft application techniques will allow quick and easy arthroscopic augmentation.

Studies of RCRs for large or massive tears have reported retear rates of 25% to 79%.^24-26 Latissimus dorsi tendon transfers also show promise in posterosuperior RCRs, with failure rates near 10%.^27,28 Although use of PHA patches in RCR augmentation is relatively new, short-term and midterm failure rates are in the range of 20% to 60% in the few small cohorts currently being studied.^13,16 It is possible that these rates may improve as indications, surgical experience, and techniques for use of PHA patches are further refined. Regardless, with PHA currently being used in practice, it is important to quantify the biomechanics of the augmentation as a baseline for its performance in reinforcing the tendon–suture interface.

We determined that the initial fixation strength of single-row repairs was higher with the addition of PHA synthetic grafts using a very simple technique. Single-row triple-loaded anchor repairs already provide high initial mechanical strength, and our results are similar to those of another study of this technique.²⁹ Despite the already high mechanical strength of a triple-loaded anchor repair, PHA mesh increased ultimate strength by about 100 N (~25%). Of note, tissue elongation during failure was higher (P = .012; power = 0.83) in the PHA-augmented group (1.2 mm) than in the nonaugmented group (0.8 mm). This was not surprising—failure loads were almost 100 N higher in the PHA-augmented group than in the nonaugmented group. Consequently, much higher forces were placed on the muscle belly, likely resulting in additional elongation of the intact tissue medial to the repair construct.

The ultimate failure loads in our study compare favorably with the biomechanical strength of augmented repairs reported by others.^8,9,18 Barber and colleagues¹⁸ evaluated an augmented single-row repair with 2 double-loaded suture anchors and an acellular dermal matrix graft. The ultimate failure load of the augmented repairs was 325 N. In contrast, Omae and colleagues⁸ tested a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft. Ultimate failure load of the augmented repairs was 560 N, similar to our finding. Last, Shea and colleagues⁹ evaluated a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft, with ultimate failure load of 429 N. The techniques in all 3 studies can be performed arthroscopically but are challenging and require multiple extra sutures and anchors that need management and tying. Our technique provides similar initial fixation strength, has no requirement for extra sutures or anchors, and is very simple to perform.

The supraspinatus tendon is estimated to fail between 800 N and 1000 N.^30,31 Biomechanical shoulder simulators use supraspinatus forces in the range of 20 N to 200 N for scapular plane abduction.^32-36 Therefore, the single-row repair failures in our study fell between functional and full-thickness failure loads. Studies on the mechanics of degenerated human supraspinatus tendon are limited, but there is evidence the mechanical properties of these tissues are inferior to those of healthy tendon.³⁷ A 100-N increase in failure loads with PHA augmentation may prove highly significant in reinforcing the suture–tendon interface in degenerated tendons.

Adding the mesh did not have any effect on gapping at the repair site after cyclic loading. This finding suggests that construct gapping under cyclic loading is not a function of a reinforced knot–tendon interface but is instead caused by microtearing and cinching of the suture constructs in relation to the underlying bone. Tissue elongation likely was not a strong contributor to overall cyclic gapping, as elongation did not differ between the nonaugmented and augmented repairs (0.5 mm vs 0.7 mm; P = .276) and was small relative to the nearly 4 mm of construct gapping. Gapping may be affected by healing and integration of the mesh into the repaired tendon over time, but this effect could not be captured in the present study. Patients are initially immobilized and passive shoulder motion gradually introduced, in stark contrast to the immediate loading protocol in the present study. Regardless, the 25% increase in overall strength may be clinically important, especially in cases of difficult repair or poor tissue quality.

Our technique simplifies arthroscopic augmentation—stitches are passed through the rotator cuff in simple fashion. Before being tied, the limbs that were passed through the rotator cuff are removed through a cannula and then passed through the synthetic graft.

Study Limitations

This study had several limitations. First, it was a cadaveric biomechanical study that evaluated only time-zero biomechanical properties. Loads were normalized to tendon size, specimens were randomized between sides, and paired specimens were used to minimize the effects of tendon and bone quality on outcome metrics. In addition, donor tendons were representative of otherwise healthy tissue. Chronic tears and associated resorption/atrophy could have affected the magnitude of forces and gapping detected in this study. Theoretically, over time the tendon tissue will adhere to and grow into the mesh, which could minimize potential differences. Studies are needed to determine the effects of healing on long-term repair strength in affected patients. Last, all constructs were performed in open fashion to improve repeatability of construct placement and provide accessibility for Instron testing. Our technique did not directly replicate the arthroscopic approach, but, unlike other augmentation techniques, it is so simple that transition to all-arthroscopic augmentation is realistic.

Patch augmentation increases the cost of materials and operative time and should be considered a limitation of its utility. We do not recommend augmentation in all RCRs, as it likely is cost-ineffective. Instead, we recommend augmentation in cases of poor tissue quality, which could lead to healing failure, revision surgery, and higher overall patient costs beyond the cost of adding augmentation. Similarly, we recommend augmentation for revision cases in which tendon healing has failed and tissue quality is poor. The goal is to prevent another failure.

Conclusion

PHA graft augmentation of single-row triple-loaded anchor repairs of the supraspinatus tendon improves the overall ultimate load to failure by 25%. There was no difference in gap formation after cyclic loading between augmented and nonaugmented repairs. This technique for arthroscopic augmentation can be used to improve initial biomechanical repair strength in tears at risk for failure.

Am J Orthop. 2016;45(7):E527-E533. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Healing after rotator cuff repair (RCR) can be challenging, especially in cases of large and massive tears, revision repairs, and tendons with poor tissue quality.^1-3 Poor tissue quality is associated with increased risk for recurrent tears, independent of age and tear size.³ Various techniques have been used to improve tendon fixation strength in these difficult situations, including augmented suture configurations (eg, massive cuff stitches, rip-stop stitches) and tissue grafts (eg, acellular dermal matrix).^4-9 Clinical studies have found improved healing rates for larger tears and revision repairs using acellular dermal matrix grafts.^6,10 Synthetic patches are another option for RCR augmentation, but limited clinical data and biomechanical evidence support use of synthetic grafts as an augment for RCRs.^11-13

Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers that have been used as orthopedic devices, tissue scaffolds, patches, and other applications with increasing frequency over the past decade.¹⁴ In the laboratory, these implanted materials have been shown to support cell migration and growth.¹⁵ The PHA family of polymers typically degrades by hydrolytic and bacterial depolymerase mechanisms over 52-plus weeks in vivo.¹⁴PHA grafts have been studied in the setting of RCR. An expanded polytetrafluoroethylene scaffold was shown to improve repair mechanics when used as a bursal side graft in an in vitro ovine model.¹¹ The graft increased tendon footprint contact pressure and failure loads by almost 180 N. In clinical studies, poly-L-lactic acid augmentations have been used to reinforce massive RCRs. Lenart and colleagues¹⁶ found that 38% of 16 patients with such tears had an intact rotator cuff at 1.2-year follow-up, and improvement in clinical scores. Proctor¹³ reported on use of a poly-L-lactic acid retrograde patch for reinforcement of massive tears with both single- and double-row repairs in 18 patients. The cohort had more favorable rates of intact cuffs at 12 months (83%) and 42 months (78%), and ASES (American Shoulder and Elbow Surgeons) scores improved from 25 before surgery to 82 at latest follow-up after surgery.

RCR augmentation traditionally has been performed with an open or mini-open technique.⁶ Recently, several authors have reported on arthroscopic techniques for augmentation with either acellular dermal matrix or synthetic grafts.^13,17,18 Most techniques have involved “bridging” with a graft or patch used to stress-shield a single-row repair.^8,9,13 This bridging typically involves placing several sutures medial to where the anchor repair stitches pass through the tendon. An alternative is to pass the repair stitches through both the tendon and the graft.^17-19 The overall volume of tissue incorporated into the repair stitches (rotator cuff plus graft) is increased with the augmented technique relative to the bridging technique. Both can be technically challenging, but the augmented technique may be easier to perform arthroscopically.^9,19 Regardless, these techniques are complicated and require a higher level of arthroscopic skills compared with those required in arthroscopic RCR without a graft. Simplifying arthroscopic graft augmentation likely will increase its utility because, even for skilled surgeons, adding a graft can increase operative time by 20 to 30 minutes. Simplification will also extend use of the technique to surgeons with less experience and proficiency with arthroscopic repair.

We developed a simple method for augmenting single-row RCR with a strip of bioresorbable soft-tissue scaffold. We also conducted a study to evaluate the initial biomechanical properties of single-row RCR in cadaveric shoulder specimens augmented with PHA mesh (BioFiber; Tornier) graft as compared with single-row RCR without augmentation. Both cyclic gap formation and ultimate failure loads and displacement were quantified. We hypothesized that the augmented RCRs would have decreased gap formation and increased ultimate failure loads compared with nonaugmented RCRs. This study was exempt from having to obtain Institutional Review Board approval.

Methods

Eight pairs of fresh-frozen cadaver humeri (6 male, 2 female; mean [SD] age, 61 [9] years) were dissected of all soft tissue (except rotator cuff) by Dr. Tashjian, a board-certified, fellowship-trained orthopedic surgeon. There were no qualitative differences in tendon condition between tendons within a pair. The supraspinatus muscle and tendon were separated from the other rotator cuff muscles. The infraspinatus, subscapularis, and teres minor were removed from the humerus. Last, the supraspinatus was resected at its insertion. Humeral pairs were then randomized into augmented and nonaugmented RCRs within each pair.

In the nonaugmented group, the supraspinatus was reattached to its insertion in a single-row RCR with 2 triple-loaded suture anchors (5.5-mm Insite FT Ti, No. 2 Force Fiber suture; Tornier) and 6 simple stitches (Figure 1A). Anchors were placed midway between the articular margin and the lateral edge of the greater tuberosity at about 45° to the bone surface.

21

Statistical Analysis

Paired t tests were used to compare the matched pairs of constructs. For all tests, significance was set at P ≤ .05. Post hoc power was calculated for significant results using G*Power Version 3.1.6.²³ All data are presented as means (SDs).

Results

After 1000 cycles of displacement, mean (SD) gapping was 3.8 (0.9) mm for the nonaugmented repairs and 3.9 (1.1) mm for the PHA mesh–augmented repairs (P = .879) (Figure 4).

For the nonaugmented repairs, mean (SD) failure displacement was 6.3 (1.7) mm, and mean (SD) ultimate failure load was 472.1 (120.3) N. For the PHA-augmented repairs, failure displacement was 5.5 (1.9) mm, and ultimate failure load was 571.2 (173.0) N. There was no difference in failure displacement (P = .393), but there was a difference in ultimate failure load (P = .042; power = 0.57). During failure testing, mean (SD) tissue deformation was higher (P = .012; power = 0.83) for the PHA-augmented repairs, 1.2 (0.7) mm, than for the nonaugmented repairs, 0.8 (0.5) mm. Failures, which were consistent within pairs, were caused by tissue failure, with sutures pulling through the tissue (4 pairs) or single anchor pullout before ultimate tissue failure (4 pairs). Of the 4 failures with anchor pullout, 3 had anterior anchor pullout, and 1 had posterior anchor pullout. In all specimens with anchor pullout, the second anchor remained stable, and ultimate failure occurred with tissue tearing at the suture interface. There were no significant differences in any metrics between specimens that failed with intact anchors and specimens with single anchor pullout (P ≥ .122). Therefore, both groups were pooled for the failure analysis.

Discussion

RCR augmentation with a synthetic graft is a viable option for improving fixation strength of supraspinatus repairs, as shown in otherwise healthy tendon in the present study. Our hypothesis that there would be decreased gap formation with graft augmentation was not supported, whereas the hypothesis of increased failure loads with graft augmentation was supported. These findings may also be applicable in cases of large tears, revisions, and tendons with poor tissue quality. Simplification of graft application techniques will allow quick and easy arthroscopic augmentation.

Studies of RCRs for large or massive tears have reported retear rates of 25% to 79%.^24-26 Latissimus dorsi tendon transfers also show promise in posterosuperior RCRs, with failure rates near 10%.^27,28 Although use of PHA patches in RCR augmentation is relatively new, short-term and midterm failure rates are in the range of 20% to 60% in the few small cohorts currently being studied.^13,16 It is possible that these rates may improve as indications, surgical experience, and techniques for use of PHA patches are further refined. Regardless, with PHA currently being used in practice, it is important to quantify the biomechanics of the augmentation as a baseline for its performance in reinforcing the tendon–suture interface.

We determined that the initial fixation strength of single-row repairs was higher with the addition of PHA synthetic grafts using a very simple technique. Single-row triple-loaded anchor repairs already provide high initial mechanical strength, and our results are similar to those of another study of this technique.²⁹ Despite the already high mechanical strength of a triple-loaded anchor repair, PHA mesh increased ultimate strength by about 100 N (~25%). Of note, tissue elongation during failure was higher (P = .012; power = 0.83) in the PHA-augmented group (1.2 mm) than in the nonaugmented group (0.8 mm). This was not surprising—failure loads were almost 100 N higher in the PHA-augmented group than in the nonaugmented group. Consequently, much higher forces were placed on the muscle belly, likely resulting in additional elongation of the intact tissue medial to the repair construct.

The ultimate failure loads in our study compare favorably with the biomechanical strength of augmented repairs reported by others.^8,9,18 Barber and colleagues¹⁸ evaluated an augmented single-row repair with 2 double-loaded suture anchors and an acellular dermal matrix graft. The ultimate failure load of the augmented repairs was 325 N. In contrast, Omae and colleagues⁸ tested a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft. Ultimate failure load of the augmented repairs was 560 N, similar to our finding. Last, Shea and colleagues⁹ evaluated a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft, with ultimate failure load of 429 N. The techniques in all 3 studies can be performed arthroscopically but are challenging and require multiple extra sutures and anchors that need management and tying. Our technique provides similar initial fixation strength, has no requirement for extra sutures or anchors, and is very simple to perform.

The supraspinatus tendon is estimated to fail between 800 N and 1000 N.^30,31 Biomechanical shoulder simulators use supraspinatus forces in the range of 20 N to 200 N for scapular plane abduction.^32-36 Therefore, the single-row repair failures in our study fell between functional and full-thickness failure loads. Studies on the mechanics of degenerated human supraspinatus tendon are limited, but there is evidence the mechanical properties of these tissues are inferior to those of healthy tendon.³⁷ A 100-N increase in failure loads with PHA augmentation may prove highly significant in reinforcing the suture–tendon interface in degenerated tendons.

Adding the mesh did not have any effect on gapping at the repair site after cyclic loading. This finding suggests that construct gapping under cyclic loading is not a function of a reinforced knot–tendon interface but is instead caused by microtearing and cinching of the suture constructs in relation to the underlying bone. Tissue elongation likely was not a strong contributor to overall cyclic gapping, as elongation did not differ between the nonaugmented and augmented repairs (0.5 mm vs 0.7 mm; P = .276) and was small relative to the nearly 4 mm of construct gapping. Gapping may be affected by healing and integration of the mesh into the repaired tendon over time, but this effect could not be captured in the present study. Patients are initially immobilized and passive shoulder motion gradually introduced, in stark contrast to the immediate loading protocol in the present study. Regardless, the 25% increase in overall strength may be clinically important, especially in cases of difficult repair or poor tissue quality.

Our technique simplifies arthroscopic augmentation—stitches are passed through the rotator cuff in simple fashion. Before being tied, the limbs that were passed through the rotator cuff are removed through a cannula and then passed through the synthetic graft.

Study Limitations

This study had several limitations. First, it was a cadaveric biomechanical study that evaluated only time-zero biomechanical properties. Loads were normalized to tendon size, specimens were randomized between sides, and paired specimens were used to minimize the effects of tendon and bone quality on outcome metrics. In addition, donor tendons were representative of otherwise healthy tissue. Chronic tears and associated resorption/atrophy could have affected the magnitude of forces and gapping detected in this study. Theoretically, over time the tendon tissue will adhere to and grow into the mesh, which could minimize potential differences. Studies are needed to determine the effects of healing on long-term repair strength in affected patients. Last, all constructs were performed in open fashion to improve repeatability of construct placement and provide accessibility for Instron testing. Our technique did not directly replicate the arthroscopic approach, but, unlike other augmentation techniques, it is so simple that transition to all-arthroscopic augmentation is realistic.

Patch augmentation increases the cost of materials and operative time and should be considered a limitation of its utility. We do not recommend augmentation in all RCRs, as it likely is cost-ineffective. Instead, we recommend augmentation in cases of poor tissue quality, which could lead to healing failure, revision surgery, and higher overall patient costs beyond the cost of adding augmentation. Similarly, we recommend augmentation for revision cases in which tendon healing has failed and tissue quality is poor. The goal is to prevent another failure.

Conclusion

PHA graft augmentation of single-row triple-loaded anchor repairs of the supraspinatus tendon improves the overall ultimate load to failure by 25%. There was no difference in gap formation after cyclic loading between augmented and nonaugmented repairs. This technique for arthroscopic augmentation can be used to improve initial biomechanical repair strength in tears at risk for failure.

Am J Orthop. 2016;45(7):E527-E533. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Healing after rotator cuff repair (RCR) can be challenging, especially in cases of large and massive tears, revision repairs, and tendons with poor tissue quality.^1-3 Poor tissue quality is associated with increased risk for recurrent tears, independent of age and tear size.³ Various techniques have been used to improve tendon fixation strength in these difficult situations, including augmented suture configurations (eg, massive cuff stitches, rip-stop stitches) and tissue grafts (eg, acellular dermal matrix).^4-9 Clinical studies have found improved healing rates for larger tears and revision repairs using acellular dermal matrix grafts.^6,10 Synthetic patches are another option for RCR augmentation, but limited clinical data and biomechanical evidence support use of synthetic grafts as an augment for RCRs.^11-13

Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers that have been used as orthopedic devices, tissue scaffolds, patches, and other applications with increasing frequency over the past decade.¹⁴ In the laboratory, these implanted materials have been shown to support cell migration and growth.¹⁵ The PHA family of polymers typically degrades by hydrolytic and bacterial depolymerase mechanisms over 52-plus weeks in vivo.¹⁴PHA grafts have been studied in the setting of RCR. An expanded polytetrafluoroethylene scaffold was shown to improve repair mechanics when used as a bursal side graft in an in vitro ovine model.¹¹ The graft increased tendon footprint contact pressure and failure loads by almost 180 N. In clinical studies, poly-L-lactic acid augmentations have been used to reinforce massive RCRs. Lenart and colleagues¹⁶ found that 38% of 16 patients with such tears had an intact rotator cuff at 1.2-year follow-up, and improvement in clinical scores. Proctor¹³ reported on use of a poly-L-lactic acid retrograde patch for reinforcement of massive tears with both single- and double-row repairs in 18 patients. The cohort had more favorable rates of intact cuffs at 12 months (83%) and 42 months (78%), and ASES (American Shoulder and Elbow Surgeons) scores improved from 25 before surgery to 82 at latest follow-up after surgery.

RCR augmentation traditionally has been performed with an open or mini-open technique.⁶ Recently, several authors have reported on arthroscopic techniques for augmentation with either acellular dermal matrix or synthetic grafts.^13,17,18 Most techniques have involved “bridging” with a graft or patch used to stress-shield a single-row repair.^8,9,13 This bridging typically involves placing several sutures medial to where the anchor repair stitches pass through the tendon. An alternative is to pass the repair stitches through both the tendon and the graft.^17-19 The overall volume of tissue incorporated into the repair stitches (rotator cuff plus graft) is increased with the augmented technique relative to the bridging technique. Both can be technically challenging, but the augmented technique may be easier to perform arthroscopically.^9,19 Regardless, these techniques are complicated and require a higher level of arthroscopic skills compared with those required in arthroscopic RCR without a graft. Simplifying arthroscopic graft augmentation likely will increase its utility because, even for skilled surgeons, adding a graft can increase operative time by 20 to 30 minutes. Simplification will also extend use of the technique to surgeons with less experience and proficiency with arthroscopic repair.

We developed a simple method for augmenting single-row RCR with a strip of bioresorbable soft-tissue scaffold. We also conducted a study to evaluate the initial biomechanical properties of single-row RCR in cadaveric shoulder specimens augmented with PHA mesh (BioFiber; Tornier) graft as compared with single-row RCR without augmentation. Both cyclic gap formation and ultimate failure loads and displacement were quantified. We hypothesized that the augmented RCRs would have decreased gap formation and increased ultimate failure loads compared with nonaugmented RCRs. This study was exempt from having to obtain Institutional Review Board approval.

Methods

Eight pairs of fresh-frozen cadaver humeri (6 male, 2 female; mean [SD] age, 61 [9] years) were dissected of all soft tissue (except rotator cuff) by Dr. Tashjian, a board-certified, fellowship-trained orthopedic surgeon. There were no qualitative differences in tendon condition between tendons within a pair. The supraspinatus muscle and tendon were separated from the other rotator cuff muscles. The infraspinatus, subscapularis, and teres minor were removed from the humerus. Last, the supraspinatus was resected at its insertion. Humeral pairs were then randomized into augmented and nonaugmented RCRs within each pair.

In the nonaugmented group, the supraspinatus was reattached to its insertion in a single-row RCR with 2 triple-loaded suture anchors (5.5-mm Insite FT Ti, No. 2 Force Fiber suture; Tornier) and 6 simple stitches (Figure 1A). Anchors were placed midway between the articular margin and the lateral edge of the greater tuberosity at about 45° to the bone surface.

21

Statistical Analysis

Paired t tests were used to compare the matched pairs of constructs. For all tests, significance was set at P ≤ .05. Post hoc power was calculated for significant results using G*Power Version 3.1.6.²³ All data are presented as means (SDs).

Results

After 1000 cycles of displacement, mean (SD) gapping was 3.8 (0.9) mm for the nonaugmented repairs and 3.9 (1.1) mm for the PHA mesh–augmented repairs (P = .879) (Figure 4).

For the nonaugmented repairs, mean (SD) failure displacement was 6.3 (1.7) mm, and mean (SD) ultimate failure load was 472.1 (120.3) N. For the PHA-augmented repairs, failure displacement was 5.5 (1.9) mm, and ultimate failure load was 571.2 (173.0) N. There was no difference in failure displacement (P = .393), but there was a difference in ultimate failure load (P = .042; power = 0.57). During failure testing, mean (SD) tissue deformation was higher (P = .012; power = 0.83) for the PHA-augmented repairs, 1.2 (0.7) mm, than for the nonaugmented repairs, 0.8 (0.5) mm. Failures, which were consistent within pairs, were caused by tissue failure, with sutures pulling through the tissue (4 pairs) or single anchor pullout before ultimate tissue failure (4 pairs). Of the 4 failures with anchor pullout, 3 had anterior anchor pullout, and 1 had posterior anchor pullout. In all specimens with anchor pullout, the second anchor remained stable, and ultimate failure occurred with tissue tearing at the suture interface. There were no significant differences in any metrics between specimens that failed with intact anchors and specimens with single anchor pullout (P ≥ .122). Therefore, both groups were pooled for the failure analysis.

Discussion

RCR augmentation with a synthetic graft is a viable option for improving fixation strength of supraspinatus repairs, as shown in otherwise healthy tendon in the present study. Our hypothesis that there would be decreased gap formation with graft augmentation was not supported, whereas the hypothesis of increased failure loads with graft augmentation was supported. These findings may also be applicable in cases of large tears, revisions, and tendons with poor tissue quality. Simplification of graft application techniques will allow quick and easy arthroscopic augmentation.

Studies of RCRs for large or massive tears have reported retear rates of 25% to 79%.^24-26 Latissimus dorsi tendon transfers also show promise in posterosuperior RCRs, with failure rates near 10%.^27,28 Although use of PHA patches in RCR augmentation is relatively new, short-term and midterm failure rates are in the range of 20% to 60% in the few small cohorts currently being studied.^13,16 It is possible that these rates may improve as indications, surgical experience, and techniques for use of PHA patches are further refined. Regardless, with PHA currently being used in practice, it is important to quantify the biomechanics of the augmentation as a baseline for its performance in reinforcing the tendon–suture interface.

We determined that the initial fixation strength of single-row repairs was higher with the addition of PHA synthetic grafts using a very simple technique. Single-row triple-loaded anchor repairs already provide high initial mechanical strength, and our results are similar to those of another study of this technique.²⁹ Despite the already high mechanical strength of a triple-loaded anchor repair, PHA mesh increased ultimate strength by about 100 N (~25%). Of note, tissue elongation during failure was higher (P = .012; power = 0.83) in the PHA-augmented group (1.2 mm) than in the nonaugmented group (0.8 mm). This was not surprising—failure loads were almost 100 N higher in the PHA-augmented group than in the nonaugmented group. Consequently, much higher forces were placed on the muscle belly, likely resulting in additional elongation of the intact tissue medial to the repair construct.

The ultimate failure loads in our study compare favorably with the biomechanical strength of augmented repairs reported by others.^8,9,18 Barber and colleagues¹⁸ evaluated an augmented single-row repair with 2 double-loaded suture anchors and an acellular dermal matrix graft. The ultimate failure load of the augmented repairs was 325 N. In contrast, Omae and colleagues⁸ tested a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft. Ultimate failure load of the augmented repairs was 560 N, similar to our finding. Last, Shea and colleagues⁹ evaluated a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft, with ultimate failure load of 429 N. The techniques in all 3 studies can be performed arthroscopically but are challenging and require multiple extra sutures and anchors that need management and tying. Our technique provides similar initial fixation strength, has no requirement for extra sutures or anchors, and is very simple to perform.

The supraspinatus tendon is estimated to fail between 800 N and 1000 N.^30,31 Biomechanical shoulder simulators use supraspinatus forces in the range of 20 N to 200 N for scapular plane abduction.^32-36 Therefore, the single-row repair failures in our study fell between functional and full-thickness failure loads. Studies on the mechanics of degenerated human supraspinatus tendon are limited, but there is evidence the mechanical properties of these tissues are inferior to those of healthy tendon.³⁷ A 100-N increase in failure loads with PHA augmentation may prove highly significant in reinforcing the suture–tendon interface in degenerated tendons.

Adding the mesh did not have any effect on gapping at the repair site after cyclic loading. This finding suggests that construct gapping under cyclic loading is not a function of a reinforced knot–tendon interface but is instead caused by microtearing and cinching of the suture constructs in relation to the underlying bone. Tissue elongation likely was not a strong contributor to overall cyclic gapping, as elongation did not differ between the nonaugmented and augmented repairs (0.5 mm vs 0.7 mm; P = .276) and was small relative to the nearly 4 mm of construct gapping. Gapping may be affected by healing and integration of the mesh into the repaired tendon over time, but this effect could not be captured in the present study. Patients are initially immobilized and passive shoulder motion gradually introduced, in stark contrast to the immediate loading protocol in the present study. Regardless, the 25% increase in overall strength may be clinically important, especially in cases of difficult repair or poor tissue quality.

Our technique simplifies arthroscopic augmentation—stitches are passed through the rotator cuff in simple fashion. Before being tied, the limbs that were passed through the rotator cuff are removed through a cannula and then passed through the synthetic graft.

Study Limitations

This study had several limitations. First, it was a cadaveric biomechanical study that evaluated only time-zero biomechanical properties. Loads were normalized to tendon size, specimens were randomized between sides, and paired specimens were used to minimize the effects of tendon and bone quality on outcome metrics. In addition, donor tendons were representative of otherwise healthy tissue. Chronic tears and associated resorption/atrophy could have affected the magnitude of forces and gapping detected in this study. Theoretically, over time the tendon tissue will adhere to and grow into the mesh, which could minimize potential differences. Studies are needed to determine the effects of healing on long-term repair strength in affected patients. Last, all constructs were performed in open fashion to improve repeatability of construct placement and provide accessibility for Instron testing. Our technique did not directly replicate the arthroscopic approach, but, unlike other augmentation techniques, it is so simple that transition to all-arthroscopic augmentation is realistic.

Patch augmentation increases the cost of materials and operative time and should be considered a limitation of its utility. We do not recommend augmentation in all RCRs, as it likely is cost-ineffective. Instead, we recommend augmentation in cases of poor tissue quality, which could lead to healing failure, revision surgery, and higher overall patient costs beyond the cost of adding augmentation. Similarly, we recommend augmentation for revision cases in which tendon healing has failed and tissue quality is poor. The goal is to prevent another failure.

Conclusion

PHA graft augmentation of single-row triple-loaded anchor repairs of the supraspinatus tendon improves the overall ultimate load to failure by 25%. There was no difference in gap formation after cyclic loading between augmented and nonaugmented repairs. This technique for arthroscopic augmentation can be used to improve initial biomechanical repair strength in tears at risk for failure.

Am J Orthop. 2016;45(7):E527-E533. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Follow-up telephone calls can significantly improve the collection of long-term patient-reported outcomes following ventral hernia repair, according to a study published online in the Oct. 20 edition of the Journal of the American College of Surgeons.

Nishant Ganesh Kumar, a medical student, and his colleagues at Vanderbilt University, Nashville, Tenn., wrote that while ventral hernia repair is one of the most common surgical procedures in the world, reliable long-term, prospective data on outcomes has been extremely difficult to collect.

copyright Dron - Fotolia.com

Follow-up telephone calls can significantly improve the collection of long-term patient-reported outcomes following ventral hernia repair, according to a study published online in the Oct. 20 edition of the Journal of the American College of Surgeons.

Nishant Ganesh Kumar, a medical student, and his colleagues at Vanderbilt University, Nashville, Tenn., wrote that while ventral hernia repair is one of the most common surgical procedures in the world, reliable long-term, prospective data on outcomes has been extremely difficult to collect.

copyright Dron - Fotolia.com

Follow-up telephone calls can significantly improve the collection of long-term patient-reported outcomes following ventral hernia repair, according to a study published online in the Oct. 20 edition of the Journal of the American College of Surgeons.

Nishant Ganesh Kumar, a medical student, and his colleagues at Vanderbilt University, Nashville, Tenn., wrote that while ventral hernia repair is one of the most common surgical procedures in the world, reliable long-term, prospective data on outcomes has been extremely difficult to collect.

copyright Dron - Fotolia.com

SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.

Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.

Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.

“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.

Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).

The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
 

Maintenance after first-line therapy

In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).

Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10^-2 cells, or MRD levels from 10^-4 to less than 10^-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.

Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.

Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.

The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.

Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.

At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.

Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10^-2 but more than 10^-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10^-2 (HR 0.165).

There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
 

Maintenance after second-line therapy

In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).

This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.

At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).

The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).

In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.

Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.

CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.

op@frontlinemedcom.com

SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.

Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.

Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.

“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.

Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).

The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
 

Maintenance after first-line therapy

In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).

Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10^-2 cells, or MRD levels from 10^-4 to less than 10^-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.

Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.

Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.

The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.

Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.

At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.

Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10^-2 but more than 10^-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10^-2 (HR 0.165).

There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
 

Maintenance after second-line therapy

In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).

This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.

At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).

The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).

In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.

Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.

CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.

op@frontlinemedcom.com

SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.

Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.

Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.

“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.

Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).

The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
 

Maintenance after first-line therapy

In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).

Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10^-2 cells, or MRD levels from 10^-4 to less than 10^-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.

Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.

Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.

The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.

Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.

At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.

Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10^-2 but more than 10^-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10^-2 (HR 0.165).

There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
 

Maintenance after second-line therapy

In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).

This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.

At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).

The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).

In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.

Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.

CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.

op@frontlinemedcom.com

WASHINGTON – Adding respiratory rate and suspected blunt chest injury to a trauma assessment in the field significantly improved the appropriate triaging of level III trauma patients.

When the assessment specifically evaluated for tachypnea in the setting of blunt chest injury, undertriaging improved by 1.2%, John Yonge, MD, said at the annual clinical congress of the American College of Surgeons.
 

“When we applied this new criteria to our 10-year study, we identified 661 patients who should have been activated as a level I or level II,” but instead were assessed as less critically injured, Dr. Yonge said in an interview. This initial misstep significantly extended the time before patients could have critical surgical procedures and was related to higher mortality among them.

Dr. Yonge, a surgical fellow at Oregon Health & Science University, Portland, and his mentor Martin Schreiber, MD, conducted the retrospective study of 7,880 trauma patients admitted at level III activation from 2004 to 2014. The OHSU trauma system has three activation levels.

• Level I activations are reserved for the most critically injured patients; attending trauma surgeon and anesthesiologist presence is mandatory.

• Level II activations capture moderate to severe injuries; trauma surgeon and respiratory therapist presence is mandated.

• Level III activations are designed to capture patients who do not require an immediate lifesaving intervention; the presence of the trauma surgery chief resident and attending emergency medicine physician is mandatory.

Patients were considered undertriaged if they were admitted as level III activations, but then required a critical intervention (chest tube placement, intubation, needle thoracostomy, or intracranial pressure monitoring) in the emergency department or ultimately met level I or II activation criteria.

Among all the level III patients, 466 (6%) were undertriaged: 390 were undertriaged based on the existing level I or II activation criteria, and 76 were considered undertriaged based on the need for a critical intervention.

Most of the undertriaged patients (65%) met criteria for level I activation; the rest should have been triaged as level II patients. Compared with appropriately staged level III patients, mortality among the undertriaged patients was significantly higher (3.2% vs. 0.6%). Undertriaged patients also experienced longer delays before initiation of major emergency surgery: a mean of 147 minutes, compared with 106 minutes for appropriately triaged level I patients and 62 minutes for appropriately triaged level II patients.

Dr. Yonge then looked for clinical measures that would improve triage. Tachypnea (respiratory rate of more than 20 breaths per minute) in the field stood out as a significant factor. Tachypneic patients who had a suspected chest injury were 70% more likely to be undertriaged than were those with a normal respiratory rate. Tachypnea was significantly associated with a diagnosis of flail chest, emergency department intubation, and chest tube placement.

The team then constructed a new triage criterion for patients with suspected chest injury – tachypnea combined with suspected blunt thoracic injury. By applying that model to their study population of level III patients, they determined that the level III undertriage rate would be reduced by 1.2%.

Tying the physiologic marker of tachypnea to a suspected clinical diagnosis is a key factor, Dr. Yonge noted. “Just adding tachypnea doesn’t help us. In fact, it would overwhelm us, because a trauma patient could very well be tachypneic because he’s experiencing panic. But tying it to a suspected clinical diagnosis gives us a meaningful result.”

He confirmed this linkage with an additional analysis. “We looked to see how severely injured these patients were and found that 71% of them had an Abbreviated Injury Score (AIS) to the chest of 3 or more, indicating a severe chest injury. Only 29% had an AIS of 2 or less. So this proves that respiratory rate is a valid triage criterion and can be used to identify patients who need a higher level of trauma care.”

The challenge now, Dr. Yonge said, is incorporating the marker into clinical practice. “It doesn’t matter how many statistics you do, if you can’t educate the prehospital providers in this, it’s useless. They are the crux of the trauma system.”

Although national guidelines do recommend assessing respiratory rate as part of field triage, it often isn’t recorded or is only estimated, Dr. Yonge said. That’s one reason he used the 20-breaths-per-minute cutoff rate. “It doesn’t even take a full minute to assess this, but it can make a big improvement in care.”

Neither he nor Dr. Schreiber had any financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Adding respiratory rate and suspected blunt chest injury to a trauma assessment in the field significantly improved the appropriate triaging of level III trauma patients.

When the assessment specifically evaluated for tachypnea in the setting of blunt chest injury, undertriaging improved by 1.2%, John Yonge, MD, said at the annual clinical congress of the American College of Surgeons.
 

“When we applied this new criteria to our 10-year study, we identified 661 patients who should have been activated as a level I or level II,” but instead were assessed as less critically injured, Dr. Yonge said in an interview. This initial misstep significantly extended the time before patients could have critical surgical procedures and was related to higher mortality among them.

Dr. Yonge, a surgical fellow at Oregon Health & Science University, Portland, and his mentor Martin Schreiber, MD, conducted the retrospective study of 7,880 trauma patients admitted at level III activation from 2004 to 2014. The OHSU trauma system has three activation levels.

• Level I activations are reserved for the most critically injured patients; attending trauma surgeon and anesthesiologist presence is mandatory.

• Level II activations capture moderate to severe injuries; trauma surgeon and respiratory therapist presence is mandated.

• Level III activations are designed to capture patients who do not require an immediate lifesaving intervention; the presence of the trauma surgery chief resident and attending emergency medicine physician is mandatory.

Patients were considered undertriaged if they were admitted as level III activations, but then required a critical intervention (chest tube placement, intubation, needle thoracostomy, or intracranial pressure monitoring) in the emergency department or ultimately met level I or II activation criteria.

Among all the level III patients, 466 (6%) were undertriaged: 390 were undertriaged based on the existing level I or II activation criteria, and 76 were considered undertriaged based on the need for a critical intervention.

Most of the undertriaged patients (65%) met criteria for level I activation; the rest should have been triaged as level II patients. Compared with appropriately staged level III patients, mortality among the undertriaged patients was significantly higher (3.2% vs. 0.6%). Undertriaged patients also experienced longer delays before initiation of major emergency surgery: a mean of 147 minutes, compared with 106 minutes for appropriately triaged level I patients and 62 minutes for appropriately triaged level II patients.

Dr. Yonge then looked for clinical measures that would improve triage. Tachypnea (respiratory rate of more than 20 breaths per minute) in the field stood out as a significant factor. Tachypneic patients who had a suspected chest injury were 70% more likely to be undertriaged than were those with a normal respiratory rate. Tachypnea was significantly associated with a diagnosis of flail chest, emergency department intubation, and chest tube placement.

The team then constructed a new triage criterion for patients with suspected chest injury – tachypnea combined with suspected blunt thoracic injury. By applying that model to their study population of level III patients, they determined that the level III undertriage rate would be reduced by 1.2%.

Tying the physiologic marker of tachypnea to a suspected clinical diagnosis is a key factor, Dr. Yonge noted. “Just adding tachypnea doesn’t help us. In fact, it would overwhelm us, because a trauma patient could very well be tachypneic because he’s experiencing panic. But tying it to a suspected clinical diagnosis gives us a meaningful result.”

He confirmed this linkage with an additional analysis. “We looked to see how severely injured these patients were and found that 71% of them had an Abbreviated Injury Score (AIS) to the chest of 3 or more, indicating a severe chest injury. Only 29% had an AIS of 2 or less. So this proves that respiratory rate is a valid triage criterion and can be used to identify patients who need a higher level of trauma care.”

The challenge now, Dr. Yonge said, is incorporating the marker into clinical practice. “It doesn’t matter how many statistics you do, if you can’t educate the prehospital providers in this, it’s useless. They are the crux of the trauma system.”

Although national guidelines do recommend assessing respiratory rate as part of field triage, it often isn’t recorded or is only estimated, Dr. Yonge said. That’s one reason he used the 20-breaths-per-minute cutoff rate. “It doesn’t even take a full minute to assess this, but it can make a big improvement in care.”

Neither he nor Dr. Schreiber had any financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Adding respiratory rate and suspected blunt chest injury to a trauma assessment in the field significantly improved the appropriate triaging of level III trauma patients.

When the assessment specifically evaluated for tachypnea in the setting of blunt chest injury, undertriaging improved by 1.2%, John Yonge, MD, said at the annual clinical congress of the American College of Surgeons.
 

“When we applied this new criteria to our 10-year study, we identified 661 patients who should have been activated as a level I or level II,” but instead were assessed as less critically injured, Dr. Yonge said in an interview. This initial misstep significantly extended the time before patients could have critical surgical procedures and was related to higher mortality among them.

Dr. Yonge, a surgical fellow at Oregon Health & Science University, Portland, and his mentor Martin Schreiber, MD, conducted the retrospective study of 7,880 trauma patients admitted at level III activation from 2004 to 2014. The OHSU trauma system has three activation levels.

• Level I activations are reserved for the most critically injured patients; attending trauma surgeon and anesthesiologist presence is mandatory.

• Level II activations capture moderate to severe injuries; trauma surgeon and respiratory therapist presence is mandated.

• Level III activations are designed to capture patients who do not require an immediate lifesaving intervention; the presence of the trauma surgery chief resident and attending emergency medicine physician is mandatory.

Patients were considered undertriaged if they were admitted as level III activations, but then required a critical intervention (chest tube placement, intubation, needle thoracostomy, or intracranial pressure monitoring) in the emergency department or ultimately met level I or II activation criteria.

Among all the level III patients, 466 (6%) were undertriaged: 390 were undertriaged based on the existing level I or II activation criteria, and 76 were considered undertriaged based on the need for a critical intervention.

Most of the undertriaged patients (65%) met criteria for level I activation; the rest should have been triaged as level II patients. Compared with appropriately staged level III patients, mortality among the undertriaged patients was significantly higher (3.2% vs. 0.6%). Undertriaged patients also experienced longer delays before initiation of major emergency surgery: a mean of 147 minutes, compared with 106 minutes for appropriately triaged level I patients and 62 minutes for appropriately triaged level II patients.

Dr. Yonge then looked for clinical measures that would improve triage. Tachypnea (respiratory rate of more than 20 breaths per minute) in the field stood out as a significant factor. Tachypneic patients who had a suspected chest injury were 70% more likely to be undertriaged than were those with a normal respiratory rate. Tachypnea was significantly associated with a diagnosis of flail chest, emergency department intubation, and chest tube placement.

The team then constructed a new triage criterion for patients with suspected chest injury – tachypnea combined with suspected blunt thoracic injury. By applying that model to their study population of level III patients, they determined that the level III undertriage rate would be reduced by 1.2%.

Tying the physiologic marker of tachypnea to a suspected clinical diagnosis is a key factor, Dr. Yonge noted. “Just adding tachypnea doesn’t help us. In fact, it would overwhelm us, because a trauma patient could very well be tachypneic because he’s experiencing panic. But tying it to a suspected clinical diagnosis gives us a meaningful result.”

He confirmed this linkage with an additional analysis. “We looked to see how severely injured these patients were and found that 71% of them had an Abbreviated Injury Score (AIS) to the chest of 3 or more, indicating a severe chest injury. Only 29% had an AIS of 2 or less. So this proves that respiratory rate is a valid triage criterion and can be used to identify patients who need a higher level of trauma care.”

The challenge now, Dr. Yonge said, is incorporating the marker into clinical practice. “It doesn’t matter how many statistics you do, if you can’t educate the prehospital providers in this, it’s useless. They are the crux of the trauma system.”

Although national guidelines do recommend assessing respiratory rate as part of field triage, it often isn’t recorded or is only estimated, Dr. Yonge said. That’s one reason he used the 20-breaths-per-minute cutoff rate. “It doesn’t even take a full minute to assess this, but it can make a big improvement in care.”

Neither he nor Dr. Schreiber had any financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

The Affordable Care Act (ACA) has greatly increased the number of Medicaid enrollees since it expanded eligibility criteria on Jan. 1, 2014. Nearly 9 million additional U.S. adults now have Medicaid coverage, mostly in the 31 states and Washington, which have opted into Medicaid expansion.

The ACA has also had an important impact on hospital payer mix, mainly by decreasing the amount of uncompensated care in Medicaid-expansion states. Previous studies have shown disparities in the quality of inpatient care based on insurance type. Patients with Medicaid insurance often have longer hospitalizations and higher in-hospital mortality than commercially-insured patients and occasionally even than uninsured patients.

University of Colorado Hospital

Mary Anderson, MD, and Christine Jones, MD, are hospitalists at the University of Colorado (Aurora) Hospital and assistant professors in the department of medicine at the University of Colorado.

The Affordable Care Act (ACA) has greatly increased the number of Medicaid enrollees since it expanded eligibility criteria on Jan. 1, 2014. Nearly 9 million additional U.S. adults now have Medicaid coverage, mostly in the 31 states and Washington, which have opted into Medicaid expansion.

The ACA has also had an important impact on hospital payer mix, mainly by decreasing the amount of uncompensated care in Medicaid-expansion states. Previous studies have shown disparities in the quality of inpatient care based on insurance type. Patients with Medicaid insurance often have longer hospitalizations and higher in-hospital mortality than commercially-insured patients and occasionally even than uninsured patients.

University of Colorado Hospital

Mary Anderson, MD, and Christine Jones, MD, are hospitalists at the University of Colorado (Aurora) Hospital and assistant professors in the department of medicine at the University of Colorado.

The Affordable Care Act (ACA) has greatly increased the number of Medicaid enrollees since it expanded eligibility criteria on Jan. 1, 2014. Nearly 9 million additional U.S. adults now have Medicaid coverage, mostly in the 31 states and Washington, which have opted into Medicaid expansion.

The ACA has also had an important impact on hospital payer mix, mainly by decreasing the amount of uncompensated care in Medicaid-expansion states. Previous studies have shown disparities in the quality of inpatient care based on insurance type. Patients with Medicaid insurance often have longer hospitalizations and higher in-hospital mortality than commercially-insured patients and occasionally even than uninsured patients.

University of Colorado Hospital

Mary Anderson, MD, and Christine Jones, MD, are hospitalists at the University of Colorado (Aurora) Hospital and assistant professors in the department of medicine at the University of Colorado.

VA Secretary Robert McDonald minced few words in his reaction to the USA Today story that published VA’s 5-star ratings for VAMCs based on its Strategic Analytics for Improvement and Learning (SAIL) data. “What concerns all of us at VA is that USA Today has a consistent narrative of negativity in their news of VA,” McDonald charged. Specifically, use of the word secret in the headline was an “egregious hyperbole,” he insisted.

Still, within days, a number of VA facilities were using the story as an opportunity to tout their success. VA Central Western Massachusetts Healthcare System in Worcester, for example, used the opportunity to tell local media that it was “in the top 10% of the 152 VA medical centers in the nation for quality of care,” and 1 of 3 5-star facilities in Massachusetts.

Other facilities, however, were forced to explain the relative nature of the 5-star scale. Keith Sullivan, director of the Chillicothe VAMC in Ohio, which received a 3-star rating, responded to reporters by noting that, “Although SAIL is a tool that helps look at areas in need of improvements, we have many other ways to ensure quality care is in place,” he said.

Many VA officials point out that the comparison to other VA facilities may be unfair, especially in underserved locations. The VA Health Care Center at Harlingen in Texas recently improved from 1 to 2 stars. It received this score, in part, because of its difficulty filling open vacancies. “Compared to the nurse retention rates in our local communities we are doing very well, [but] not so much as compared to other VA health care systems in the nation,” a Harlingen customer service manager told a local newspaper.

To allay veterans’ fears, the VA Southern Oregon Rehabilitation Center and Clinics (VA SORCC) sent out a news release to explain the ratings and reassure the public that progress was being made even as it struggles with a shortage of providers. Insisting it had made “absolute performance improvements in wait times for both mental health and specialty care appointments” while acknowledging that the rating also shows “continued frustrations with difficulty in navigating the system and with coordination of care." These frustrations impact Veterans’ experience at the facility, leading to lower scores.” The release pledged that “VA SORCC is currently a 1-star facility but fully expects to move to a 2-star facility in the next quarter.”

The worry for many at the VA is that the veterans might avoid 1- and 2-star facilities. “My concern is that veterans are going to see that their hospital is a ‘one’ in our star system, assume that’s bad quality and veterans that need care are not going to get care,” VA Under Secretary of Health David J. Shulkin, MD, told USA Today. “And they’re going to stay away from hospitals and that’s going to hurt people.”

VA Secretary Robert McDonald minced few words in his reaction to the USA Today story that published VA’s 5-star ratings for VAMCs based on its Strategic Analytics for Improvement and Learning (SAIL) data. “What concerns all of us at VA is that USA Today has a consistent narrative of negativity in their news of VA,” McDonald charged. Specifically, use of the word secret in the headline was an “egregious hyperbole,” he insisted.

Still, within days, a number of VA facilities were using the story as an opportunity to tout their success. VA Central Western Massachusetts Healthcare System in Worcester, for example, used the opportunity to tell local media that it was “in the top 10% of the 152 VA medical centers in the nation for quality of care,” and 1 of 3 5-star facilities in Massachusetts.

Other facilities, however, were forced to explain the relative nature of the 5-star scale. Keith Sullivan, director of the Chillicothe VAMC in Ohio, which received a 3-star rating, responded to reporters by noting that, “Although SAIL is a tool that helps look at areas in need of improvements, we have many other ways to ensure quality care is in place,” he said.

Many VA officials point out that the comparison to other VA facilities may be unfair, especially in underserved locations. The VA Health Care Center at Harlingen in Texas recently improved from 1 to 2 stars. It received this score, in part, because of its difficulty filling open vacancies. “Compared to the nurse retention rates in our local communities we are doing very well, [but] not so much as compared to other VA health care systems in the nation,” a Harlingen customer service manager told a local newspaper.

To allay veterans’ fears, the VA Southern Oregon Rehabilitation Center and Clinics (VA SORCC) sent out a news release to explain the ratings and reassure the public that progress was being made even as it struggles with a shortage of providers. Insisting it had made “absolute performance improvements in wait times for both mental health and specialty care appointments” while acknowledging that the rating also shows “continued frustrations with difficulty in navigating the system and with coordination of care." These frustrations impact Veterans’ experience at the facility, leading to lower scores.” The release pledged that “VA SORCC is currently a 1-star facility but fully expects to move to a 2-star facility in the next quarter.”

The worry for many at the VA is that the veterans might avoid 1- and 2-star facilities. “My concern is that veterans are going to see that their hospital is a ‘one’ in our star system, assume that’s bad quality and veterans that need care are not going to get care,” VA Under Secretary of Health David J. Shulkin, MD, told USA Today. “And they’re going to stay away from hospitals and that’s going to hurt people.”

VA Secretary Robert McDonald minced few words in his reaction to the USA Today story that published VA’s 5-star ratings for VAMCs based on its Strategic Analytics for Improvement and Learning (SAIL) data. “What concerns all of us at VA is that USA Today has a consistent narrative of negativity in their news of VA,” McDonald charged. Specifically, use of the word secret in the headline was an “egregious hyperbole,” he insisted.

Still, within days, a number of VA facilities were using the story as an opportunity to tout their success. VA Central Western Massachusetts Healthcare System in Worcester, for example, used the opportunity to tell local media that it was “in the top 10% of the 152 VA medical centers in the nation for quality of care,” and 1 of 3 5-star facilities in Massachusetts.

Other facilities, however, were forced to explain the relative nature of the 5-star scale. Keith Sullivan, director of the Chillicothe VAMC in Ohio, which received a 3-star rating, responded to reporters by noting that, “Although SAIL is a tool that helps look at areas in need of improvements, we have many other ways to ensure quality care is in place,” he said.

Many VA officials point out that the comparison to other VA facilities may be unfair, especially in underserved locations. The VA Health Care Center at Harlingen in Texas recently improved from 1 to 2 stars. It received this score, in part, because of its difficulty filling open vacancies. “Compared to the nurse retention rates in our local communities we are doing very well, [but] not so much as compared to other VA health care systems in the nation,” a Harlingen customer service manager told a local newspaper.

To allay veterans’ fears, the VA Southern Oregon Rehabilitation Center and Clinics (VA SORCC) sent out a news release to explain the ratings and reassure the public that progress was being made even as it struggles with a shortage of providers. Insisting it had made “absolute performance improvements in wait times for both mental health and specialty care appointments” while acknowledging that the rating also shows “continued frustrations with difficulty in navigating the system and with coordination of care." These frustrations impact Veterans’ experience at the facility, leading to lower scores.” The release pledged that “VA SORCC is currently a 1-star facility but fully expects to move to a 2-star facility in the next quarter.”

The worry for many at the VA is that the veterans might avoid 1- and 2-star facilities. “My concern is that veterans are going to see that their hospital is a ‘one’ in our star system, assume that’s bad quality and veterans that need care are not going to get care,” VA Under Secretary of Health David J. Shulkin, MD, told USA Today. “And they’re going to stay away from hospitals and that’s going to hurt people.”

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—Daratumumab added to standard of care regimens drives deep clinical responses beyond complete response (CR), a magnitude that is “unprecedented” in the relapsed/refractory multiple myeloma (MM) setting, according to a speaker at the 2016 ASH Annual Meeting.

Investigators added daratumumab to lenalidomide/dexamethasone in the POLLUX trial and to bortezomib/dexamethasone in the CASTOR trial.

In both phase 3 trials, the addition of daratumumab resulted in significant improvements in progression-free survival (PFS), overall response rate, and minimal residual disease (MRD) negativity when compared to control groups.

“The magnitude of daratumumab-induced MRD negativity in the relapsed setting is unprecedented and, for me, was not expected,” said Hervé Avet-Loiseau, MD, of Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome in Toulouse, France.

Dr Avet-Loiseau presented the MRD findings from CASTOR and POLLUX at the ASH Annual Meeting as abstract 246.*

He noted that, based on these studies, daratumumab received US Food and Drug Administration approvals for use in combination with standard of care regimens for MM patients who had received 1 or more prior lines of treatment.

Daratumumab had been previously approved as monotherapy for relapsed or refractory MM.

Study designs and findings from the POLLUX and CASTOR trials have been described earlier in Hematology Times.

Dr Avet-Loiseau provided updated PFS figures for the 2 studies.

At 18 months’ follow-up in the POLLUX study, the PFS rate for patients treated with daratumumab/lenalidomide/dexamethasone was 76%, compared to 49% in the lenalidomide/dexamethasone arm (P<0.0001).

At 12 months’ follow-up in the CASTOR study, the PFS with daratumumab was 60%, compared to 22% for bortezomib/dexamethasone (P<0.0001).

MRD criteria

In both studies, MRD assessments were conducted at suspected complete response (CR). Assessments were also conducted at 3 months and 6 months after CR in the POLLUX study and at 6 months and 12 months after the first study dose in the CASTOR study.

For the assessment of MRD, investigators used bone marrow aspirate samples and the ClonoSEQ^TM NGS-based assay.

Investigators evaluated MRD at 3 sensitivity thresholds: 10^-4, 10^-5, and 10^-6.

And they used a stringent, unbiased evaluation, Dr Avet-Loiseau said. Any patient in the intent-to-treat population who was not assessed to be MRD negative was scored as MRD positive.

And the minimum cell input equivalent to the sensitivity threshold was required to determine MRD negativity.

MRD results

In the POLLUX study, 24.8% of patients achieved MRD negativity at the 10^-5 cutoff, and 11.9% achieved MRD negativity at the 10^-6 cutoff with the daratumumab combination.

This compared to 5.7% and 2.5% MRD negativity at the 10^-5 and 10^-6 cutoffs, respectively, without daratumumab (P<0.0001).

In the CASTOR study, the daratumumab-treated patients achieved 10.4% and 4.4% MRD negativity at the 10^-5 and 10^-6 cutoffs, respectively.

This compared to 2.4% and 0.8% MRD negativity in the control arm at the 10^-5 and 10^-6 cutoffs (P<0.005 and P<0.05), respectively.

“So, definitely, the addition of daratumumab improved the MRD negativity rate in both studies,” Dr Avet-Loiseau said.

“If you just look at the patients who did achieve CR in the POLLUX study, almost 50% of the patients [treated with daratumumab] achieved CR, and half of them were MRD negative at the cutoff of 10^-5.”

In the CASTOR study, 25% of the patients treated with daratumumab achieved a CR. The MRD negativity rate was one-third in these patients.

“So again, we have consistently higher MRD negative rates in patients who achieve CR when they were treated in the daratumumab arms,” Dr Avet-Loiseau said.

“What is interesting, I think, is that the achievement of molecular CR was very rapid. [A]t 3 months, some patients did already achieve MRD negativity, and so we continued to see an improvement. [W]e still continue to see some achievement of MRD negativity.”

Investigators continue to follow the patients annually.

The investigators also analyzed MRD at 10^-5 by cytogenetic risk and did not observe any MRD negativity in the control arm in either the POLLUX or CASTOR study.

“In contrast, we did observe some significant MRD negativity in the experimental arm with daratumumab—18% (POLLUX) and 14% (CASTOR) in high-risk patients,” Dr Avet-Loiseau said. “The most important prognostic factor is to achieve MRD negativity.”

However, even for patients who did not achieve MRD negativity, the PFS was much better in the experimental arms than in the control arms, he added.

This study, presented as a “Best of ASH” abstract, was funded by Janssen Research & Development, LLC.

*Information in the abstract differs from that presented at the meeting.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—Daratumumab added to standard of care regimens drives deep clinical responses beyond complete response (CR), a magnitude that is “unprecedented” in the relapsed/refractory multiple myeloma (MM) setting, according to a speaker at the 2016 ASH Annual Meeting.

Investigators added daratumumab to lenalidomide/dexamethasone in the POLLUX trial and to bortezomib/dexamethasone in the CASTOR trial.

In both phase 3 trials, the addition of daratumumab resulted in significant improvements in progression-free survival (PFS), overall response rate, and minimal residual disease (MRD) negativity when compared to control groups.

“The magnitude of daratumumab-induced MRD negativity in the relapsed setting is unprecedented and, for me, was not expected,” said Hervé Avet-Loiseau, MD, of Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome in Toulouse, France.

Dr Avet-Loiseau presented the MRD findings from CASTOR and POLLUX at the ASH Annual Meeting as abstract 246.*

He noted that, based on these studies, daratumumab received US Food and Drug Administration approvals for use in combination with standard of care regimens for MM patients who had received 1 or more prior lines of treatment.

Daratumumab had been previously approved as monotherapy for relapsed or refractory MM.

Study designs and findings from the POLLUX and CASTOR trials have been described earlier in Hematology Times.

Dr Avet-Loiseau provided updated PFS figures for the 2 studies.

At 18 months’ follow-up in the POLLUX study, the PFS rate for patients treated with daratumumab/lenalidomide/dexamethasone was 76%, compared to 49% in the lenalidomide/dexamethasone arm (P<0.0001).

At 12 months’ follow-up in the CASTOR study, the PFS with daratumumab was 60%, compared to 22% for bortezomib/dexamethasone (P<0.0001).

MRD criteria

In both studies, MRD assessments were conducted at suspected complete response (CR). Assessments were also conducted at 3 months and 6 months after CR in the POLLUX study and at 6 months and 12 months after the first study dose in the CASTOR study.

For the assessment of MRD, investigators used bone marrow aspirate samples and the ClonoSEQ^TM NGS-based assay.

Investigators evaluated MRD at 3 sensitivity thresholds: 10^-4, 10^-5, and 10^-6.

And they used a stringent, unbiased evaluation, Dr Avet-Loiseau said. Any patient in the intent-to-treat population who was not assessed to be MRD negative was scored as MRD positive.

And the minimum cell input equivalent to the sensitivity threshold was required to determine MRD negativity.

MRD results

In the POLLUX study, 24.8% of patients achieved MRD negativity at the 10^-5 cutoff, and 11.9% achieved MRD negativity at the 10^-6 cutoff with the daratumumab combination.

This compared to 5.7% and 2.5% MRD negativity at the 10^-5 and 10^-6 cutoffs, respectively, without daratumumab (P<0.0001).

In the CASTOR study, the daratumumab-treated patients achieved 10.4% and 4.4% MRD negativity at the 10^-5 and 10^-6 cutoffs, respectively.

This compared to 2.4% and 0.8% MRD negativity in the control arm at the 10^-5 and 10^-6 cutoffs (P<0.005 and P<0.05), respectively.

“So, definitely, the addition of daratumumab improved the MRD negativity rate in both studies,” Dr Avet-Loiseau said.

“If you just look at the patients who did achieve CR in the POLLUX study, almost 50% of the patients [treated with daratumumab] achieved CR, and half of them were MRD negative at the cutoff of 10^-5.”

In the CASTOR study, 25% of the patients treated with daratumumab achieved a CR. The MRD negativity rate was one-third in these patients.

“So again, we have consistently higher MRD negative rates in patients who achieve CR when they were treated in the daratumumab arms,” Dr Avet-Loiseau said.

“What is interesting, I think, is that the achievement of molecular CR was very rapid. [A]t 3 months, some patients did already achieve MRD negativity, and so we continued to see an improvement. [W]e still continue to see some achievement of MRD negativity.”

Investigators continue to follow the patients annually.

The investigators also analyzed MRD at 10^-5 by cytogenetic risk and did not observe any MRD negativity in the control arm in either the POLLUX or CASTOR study.

“In contrast, we did observe some significant MRD negativity in the experimental arm with daratumumab—18% (POLLUX) and 14% (CASTOR) in high-risk patients,” Dr Avet-Loiseau said. “The most important prognostic factor is to achieve MRD negativity.”

However, even for patients who did not achieve MRD negativity, the PFS was much better in the experimental arms than in the control arms, he added.

This study, presented as a “Best of ASH” abstract, was funded by Janssen Research & Development, LLC.

*Information in the abstract differs from that presented at the meeting.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—Daratumumab added to standard of care regimens drives deep clinical responses beyond complete response (CR), a magnitude that is “unprecedented” in the relapsed/refractory multiple myeloma (MM) setting, according to a speaker at the 2016 ASH Annual Meeting.

Investigators added daratumumab to lenalidomide/dexamethasone in the POLLUX trial and to bortezomib/dexamethasone in the CASTOR trial.

In both phase 3 trials, the addition of daratumumab resulted in significant improvements in progression-free survival (PFS), overall response rate, and minimal residual disease (MRD) negativity when compared to control groups.

“The magnitude of daratumumab-induced MRD negativity in the relapsed setting is unprecedented and, for me, was not expected,” said Hervé Avet-Loiseau, MD, of Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome in Toulouse, France.

Dr Avet-Loiseau presented the MRD findings from CASTOR and POLLUX at the ASH Annual Meeting as abstract 246.*

He noted that, based on these studies, daratumumab received US Food and Drug Administration approvals for use in combination with standard of care regimens for MM patients who had received 1 or more prior lines of treatment.

Daratumumab had been previously approved as monotherapy for relapsed or refractory MM.

Study designs and findings from the POLLUX and CASTOR trials have been described earlier in Hematology Times.

Dr Avet-Loiseau provided updated PFS figures for the 2 studies.

At 18 months’ follow-up in the POLLUX study, the PFS rate for patients treated with daratumumab/lenalidomide/dexamethasone was 76%, compared to 49% in the lenalidomide/dexamethasone arm (P<0.0001).

At 12 months’ follow-up in the CASTOR study, the PFS with daratumumab was 60%, compared to 22% for bortezomib/dexamethasone (P<0.0001).

MRD criteria

In both studies, MRD assessments were conducted at suspected complete response (CR). Assessments were also conducted at 3 months and 6 months after CR in the POLLUX study and at 6 months and 12 months after the first study dose in the CASTOR study.

For the assessment of MRD, investigators used bone marrow aspirate samples and the ClonoSEQ^TM NGS-based assay.

Investigators evaluated MRD at 3 sensitivity thresholds: 10^-4, 10^-5, and 10^-6.

And they used a stringent, unbiased evaluation, Dr Avet-Loiseau said. Any patient in the intent-to-treat population who was not assessed to be MRD negative was scored as MRD positive.

And the minimum cell input equivalent to the sensitivity threshold was required to determine MRD negativity.

MRD results

In the POLLUX study, 24.8% of patients achieved MRD negativity at the 10^-5 cutoff, and 11.9% achieved MRD negativity at the 10^-6 cutoff with the daratumumab combination.

This compared to 5.7% and 2.5% MRD negativity at the 10^-5 and 10^-6 cutoffs, respectively, without daratumumab (P<0.0001).

In the CASTOR study, the daratumumab-treated patients achieved 10.4% and 4.4% MRD negativity at the 10^-5 and 10^-6 cutoffs, respectively.

This compared to 2.4% and 0.8% MRD negativity in the control arm at the 10^-5 and 10^-6 cutoffs (P<0.005 and P<0.05), respectively.

“So, definitely, the addition of daratumumab improved the MRD negativity rate in both studies,” Dr Avet-Loiseau said.

“If you just look at the patients who did achieve CR in the POLLUX study, almost 50% of the patients [treated with daratumumab] achieved CR, and half of them were MRD negative at the cutoff of 10^-5.”

In the CASTOR study, 25% of the patients treated with daratumumab achieved a CR. The MRD negativity rate was one-third in these patients.

“So again, we have consistently higher MRD negative rates in patients who achieve CR when they were treated in the daratumumab arms,” Dr Avet-Loiseau said.

“What is interesting, I think, is that the achievement of molecular CR was very rapid. [A]t 3 months, some patients did already achieve MRD negativity, and so we continued to see an improvement. [W]e still continue to see some achievement of MRD negativity.”

Investigators continue to follow the patients annually.

The investigators also analyzed MRD at 10^-5 by cytogenetic risk and did not observe any MRD negativity in the control arm in either the POLLUX or CASTOR study.

“In contrast, we did observe some significant MRD negativity in the experimental arm with daratumumab—18% (POLLUX) and 14% (CASTOR) in high-risk patients,” Dr Avet-Loiseau said. “The most important prognostic factor is to achieve MRD negativity.”

However, even for patients who did not achieve MRD negativity, the PFS was much better in the experimental arms than in the control arms, he added.

This study, presented as a “Best of ASH” abstract, was funded by Janssen Research & Development, LLC.

*Information in the abstract differs from that presented at the meeting.

Child with cancer

Photo by Bill Branson

SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).

These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.

However, the upper age limit for this strategy has not been defined.

With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.

Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.

The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.

They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.

Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).

GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.

Study design

Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.

Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.

Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.

During induction and late intensification, patients received cyclophosphamide at 750 mg/m² on day 1 and were then randomized to hyper-C (300 mg/m²/every 12 hours on days 15 to 17) or standard-C (750 mg/m² on day 15).

The primary endpoint was EFS.

Patient population

Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.

Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.

Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.

About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.

Results

The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.

Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.

Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10^-4.

There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.

The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).

Impact of age

Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).

Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).

Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.

The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.

And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.

“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”

Treatment compliance

In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).

During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.

And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.

EFS by age and randomization

The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).

However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).

Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”

Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”

She added that patients over 54 might benefit from alternative front-line strategies.

Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.

Child with cancer

Photo by Bill Branson

SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).

These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.

However, the upper age limit for this strategy has not been defined.

With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.

Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.

The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.

They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.

Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).

GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.

Study design

Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.

Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.

Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.

During induction and late intensification, patients received cyclophosphamide at 750 mg/m² on day 1 and were then randomized to hyper-C (300 mg/m²/every 12 hours on days 15 to 17) or standard-C (750 mg/m² on day 15).

The primary endpoint was EFS.

Patient population

Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.

Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.

Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.

About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.

Results

The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.

Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.

Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10^-4.

There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.

The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).

Impact of age

Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).

Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).

Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.

The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.

And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.

“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”

Treatment compliance

In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).

During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.

And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.

EFS by age and randomization

The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).

However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).

Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”

Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”

She added that patients over 54 might benefit from alternative front-line strategies.

Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.

Child with cancer

Photo by Bill Branson

SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).

These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.

However, the upper age limit for this strategy has not been defined.

With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.

Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.

The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.

They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.

Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).

GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.

Study design

Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.

Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.

Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.

During induction and late intensification, patients received cyclophosphamide at 750 mg/m² on day 1 and were then randomized to hyper-C (300 mg/m²/every 12 hours on days 15 to 17) or standard-C (750 mg/m² on day 15).

The primary endpoint was EFS.

Patient population

Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.

Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.

Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.

About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.

Results

The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.

Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.

Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10^-4.

There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.

The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).

Impact of age

Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).

Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).

Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.

The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.

And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.

“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”

Treatment compliance

In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).

During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.

And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.

EFS by age and randomization

The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).

However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).

Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”

Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”

She added that patients over 54 might benefit from alternative front-line strategies.

Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).

The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.

However, the fusion genes alone are not capable of causing CBF-AML.

“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”

Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).

A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.

For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.

The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.

Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.

The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.

CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.

The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.

In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.

“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).

The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.

However, the fusion genes alone are not capable of causing CBF-AML.

“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”

Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).

A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.

For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.

The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.

Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.

The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.

CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.

The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.

In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.

“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).

The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.

However, the fusion genes alone are not capable of causing CBF-AML.

“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”

Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).

A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.

For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.

The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.

Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.

The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.

CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.

The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.

In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.

“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”

Ofatumumab (Arzerra)

Photo courtesy of GSK

The European Commission (EC) has granted marketing authorization for ofatumumab (Arzerra®) to be used in combination with fludarabine and cyclophosphamide (FC) in the treatment of adults with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.

The EC previously authorized the use of ofatumumab as a single agent to treat CLL patients who are refractory to fludarabine and alemtuzumab.

The agency also authorized the use of ofatumumab in combination with chlorambucil or bendamustine in CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy.

The EC’s decision to approve the use of ofatumumab in combination with FC was based on results from the phase 3 COMPLEMENT 2 study, which were published in Leukemia & Lymphoma in October.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with FC or up to 6 cycles of FC alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus FC, compared to 18.8 months for patients receiving FC only (hazard ratio=0.67, P=0.0032).

The incidence of grade 3 or higher adverse events was 74% in the ofatumumab-plus-FC arm and 69% in the FC-only arm. Neutropenia was the most common of these events, occurring in 49% and 36% of patients, respectively.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The European Commission (EC) has granted marketing authorization for ofatumumab (Arzerra®) to be used in combination with fludarabine and cyclophosphamide (FC) in the treatment of adults with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.

The EC previously authorized the use of ofatumumab as a single agent to treat CLL patients who are refractory to fludarabine and alemtuzumab.

The agency also authorized the use of ofatumumab in combination with chlorambucil or bendamustine in CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy.

The EC’s decision to approve the use of ofatumumab in combination with FC was based on results from the phase 3 COMPLEMENT 2 study, which were published in Leukemia & Lymphoma in October.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with FC or up to 6 cycles of FC alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus FC, compared to 18.8 months for patients receiving FC only (hazard ratio=0.67, P=0.0032).

The incidence of grade 3 or higher adverse events was 74% in the ofatumumab-plus-FC arm and 69% in the FC-only arm. Neutropenia was the most common of these events, occurring in 49% and 36% of patients, respectively.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The European Commission (EC) has granted marketing authorization for ofatumumab (Arzerra®) to be used in combination with fludarabine and cyclophosphamide (FC) in the treatment of adults with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.

The EC previously authorized the use of ofatumumab as a single agent to treat CLL patients who are refractory to fludarabine and alemtuzumab.

The agency also authorized the use of ofatumumab in combination with chlorambucil or bendamustine in CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy.

The EC’s decision to approve the use of ofatumumab in combination with FC was based on results from the phase 3 COMPLEMENT 2 study, which were published in Leukemia & Lymphoma in October.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with FC or up to 6 cycles of FC alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus FC, compared to 18.8 months for patients receiving FC only (hazard ratio=0.67, P=0.0032).

The incidence of grade 3 or higher adverse events was 74% in the ofatumumab-plus-FC arm and 69% in the FC-only arm. Neutropenia was the most common of these events, occurring in 49% and 36% of patients, respectively.