In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new “basket” clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.
Purpose/Objective
To evaluate local control following surgical resection and postoperative stereotactic radiosurgery (SRS) for brain metastases.
Methods and Materials
Forty-nine patients (50 lesions) were enrolled and available for analysis. Eligibility criteria included histologically confirmed malignancy with 1 or 2 intraparenchymal brain metastases, age ≥18, and KPS ≥70. Cox proportional hazard regression model was used to test for significant association between clinical factors and overall survival (OS). Competing risks regression models, as well as cumulative incidence functions, were fit using the method of Fine and Gray in order to assess the association between clinical factors and both local failure (LF, recurrence within surgical cavity or SRS target), and regional failure (RF, intracranial metastasis outside of treated volume).
Results
The median follow-up was 12.0 months (mos, range: 1.0–94.1 mos). Following surgical resection, 39 patients with 40 lesions were treated a median of 31 days (range: 7–56 days) later with SRS to the surgical bed to a median dose of 1800 cGy (range: 1500–2200 cGy). Of the 50 lesions, 15 (30%) demonstrated LF after surgery. The cumulative LF and RF rates were 22% and 44% at 12 mos. Patients who went on to receive SRS had significantly lower incidence of LF (p=0.008). Other factors associated with improved local control includes NSCLC histology (p=0.048), tumor diameter <3 cm (p=0.010), and deep parenchymal tumors (p=0.036). Large tumors (≥3 cm) with superficial dural/pial involvement showed the highest risk for LF (53.3% at 12 mos). Large, superficial lesions treated with SRS had 54.5% LF. Infratentorial lesions were at higher risk of developing RF compared to supratentorial lesions (p <0.001).
Conclusions
Postoperative SRS is associated with high local control, especially for deep brain metastases <3 cm. Tumors ≥3 cm with superficial dural/pial involvement demonstrate the highest risk in LF.
Key Points• ST2 is independently associated with aGVHD after day 28 in cord blood transplantation recipients.• High ST2 levels predict for increased TRM in cord blood transplantation recipients.While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P 5 .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P 5 .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating isletderived protein 3-a were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT. (Blood. 2015;125(1):199-205)
Key Points
Carfilzomib 56 mg/m2 provided a high overall response rate with a remarkable duration of response in patients with R/RMM. Nonhematologic grade 3/4 AEs likely related to carfilzomib treatment included hypertension and heart failure.
While mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit CBT (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 double-unit CBT recipients (median age 39 years, range 1–71) transplanted for hematologic malignancies. Recipients of a MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III-IV acute GVHD (aGVHD) incidence compared with patients who received > 36 mg/kg/day (24% versus 8%, p = 0.008). Recipients of ≤ the median dose who had highly HLA-allele (1-3/6) mismatched dominant units had the highest day 100 grade III-IV aGVHD incidence of 37% (p = 0.009). This finding was confirmed in multivariate analysis (p = 0.053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1-2 trough < 0.5 mcg/mL had an increased day 100 grade III-IV aGVHD of 26% versus 9% (p = 0.063), and those who received a low total daily MMF dose and had a low week 1-2 MPA trough had a 40% incidence (p = 0.008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in mg/kg/day and MPA trough level monitoring early post-transplant in dCBT recipients.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). Donor T cells are critical for graft-versus-tumor effect (GVT) but carry the risk of graft-versus-host disease (GVHD). CD34 selection with immunomagnetic beads has been an effective method of depleting alloreactive donor T cells from the peripheral blood graft and has been shown to result in significant reduction in acute and chronic GVHD. We analyzed the outcomes of 102 adults (median age 57.6 years) with advanced MDS who received a CD34 selected allo-HSCT between January 1997 and April 2012 at Memorial Sloan Kettering Cancer Center. The cumulative incidence (CI) of grade II-IV acute GVHD at day 100 was 9.8% (95% CI: 5.0-16.5%) and at day 180, 15.7% (95% CI: 9.4-23.4%). The CI of chronic GVHD at 1 year was 3.9% (95% CI: 1.3-9.0%). The CI of relapse at 1 year was 11.8% (95% CI: 6.4-18.9%) and at 2 years 15.7% (95% CI: 9.4-23.4%). Forty-eight patients were alive with a median follow-up of 71.7 months. The overall survival (OS) at 2 years was 56.9% (95% CI: 48-67.3%) and at 5 years, 49.3% (95% CI: 40.4-60.2%). Relapse-free survival (RFS) at 2 years was 52.0% (95% CI: 41.9-61.1%) and at 5 years, 47.6% (95% CI: 37.5-56.9%). The CI of non-relapse mortality was 7.8% (95% CI: 3.7-14.1%) at day 100, 22.5% (95% CI 15.0-31.1%) at 1 year and 33.4% (95% CI:24.2-42.6%) at 5 years post-transplant. Chronic GVHD/relapse-free survival (CRFS) overlapped with RFS. These findings demonstrate that ex-vivo T- cell depleted (TCD) allo-HSCT by CD34 selection offers long term OS and RFS with low incidences of acute and chronic GVHD and without an increased risk of relapse.
Ex vivo CD34+ selected T-cell depletion (TCD) has been developed as a strategy to reduce the incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Clinical characteristics, treatment responses, and outcomes of patients developing acute (a-) and chronic (c-) GVHD after TCD allo-HSCT have not been well established. We evaluated 241 consecutive patients (median age 57 years) with acute leukemia (n = 191, 79%) or myelodysplastic syndrome (MDS) (n = 50, 21%) undergoing CD34+ selected TCD allo-HSCT without post-HCST immunosuppression in a single institution. Cumulative incidences of grade II–IV and III–IV aGVHD at 180 days were 16% (95% CI:12–21) and 5% (95% CI:3–9), respectively. The skin was the most frequent organ involved, followed by the GI tract. Patients were treated with topical corticosteroids, poorly absorbed corticosteroids (Budesonide), and/or systemic corticosteroids. The overall day 28 treatment response was high at 82%. Cumulative incidence of any cGVHD at 3 years was 5% (95% CI:3–9), with a median time of onset of 256 days (range 95–1645). The 3-year transplant-related mortality, relapse, overall survival and disease-free survival were 24% (95%CI: 18–30), 22% (95% CI:17–27), 57% (95% CI:50–64) and 54% (95% CI:47–61), respectively. The 1-year and 3-years probability of cGVHD-free/relapse-free survival (CRFS) were 65% (95% CI:59–71) and 52% (95% CI:45–59), respectively. Our findings support the use of ex vivo CD34+ selected TCD allograft as a calcineurin inhibitor-free intervention for the prevention of GVHD in patients with acute leukemia and MDS.
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