Introduction: The majority of patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities at diagnosis or when treatment is needed. However, impact of comorbidities on CLL treatment outcomes remains understudied, as such patients are typically excluded from clinical trials. While multiple regimens have been approved for treatment of CLL, only few have been evaluated in this patient population. Furthermore, assessment of comorbidities in CLL has not been standardized. Several recent studies have assessed Cumulative Illness Rating Scale (CIRS) score at enrollment. Thus, in this retrospective analysis, we evaluate CIRS score and analyze whether it is predictive of treatment outcomes in CLL. Methods: We performed a retrospective analysis of CLL patients treated at Dartmouth between 2000 and 2013. CIRS score was calculated as in Salvi et al, 2008. Overall survival (OS) and progression-free survival (PFS) were assessed by using Cox proportional hazards models adjusting for performance status, age group, and chemotherapy treatments. In addition, the impact of severe organ dysfunction (CIRS 3-4 in ≥1 organ system, referred to as "CIRS-3+") was assessed. Results:133 patients received a total of 255 treatment regimens. Median age at the start of therapy was 65. Fludarabine (Flu)-Rituximab (FR, N=52), Fludarabine-Cyclophosphamide-Rituximab (FCR, N=30), Rituximab-Cyclophosphamide-Vincristine-Prednisone (R-CVP, N=35), Bendamustine-Rituximab (BR, N=30) and chlorambucil (Chl; N=25) were the most commonly used treatment regimens. 65.6% of treatments were administered in a frontline setting. Specifically, 77%, 73%, 63%, 33%, and 76% of patients received the above regimens as frontline therapy, correspondingly. Median OS among all patients was 126.1±12.2 months. 53% of patients had CIRS≥7 and 57% had CIRS-3+. Their respective median OS were 106.1±12.2 and 108.5±3.7 months (p<0.05 compared to patients with CIRS<7, at 128.2±1.4 months). In this retrospective analysis, CIRS score did not predict the choice of therapy. Age over 70 was associated with a decreased likelihood of receiving Flu (OR=0.2, p=0.017), while Chl was used more frequently in this patient population (OR=45.26, p<0.001). Multivariate analysis of a total CIRS score, age and performance status (PS) demonstrated that OS after CLL therapy shortened with each increase in total CIRS score by one point (HR=1.12; p=0.02). Multivariate analysis of CIRS-3+, PS, and age demonstrated that OS after therapy worsened with an increase in number of organ systems affected by a severe (grade 3-4) comorbidity (HR=1.58, p=0.04). Patients>70 year old had worse OS in multivariate analysis of CIRS≥7, CIRS-3+, age and PS. Interestingly, higher total CIRS, presence of a severe organ dysfunction (CIRS-3+) as well as CIRS≥7 were all significant predictors of decreased PFS. Among therapies used, Flu and cyclophosphamide-based regimens were associated with decreased OS in patients with CIRS≥7 (HR=6.5, p=0.01 and HR=10.4, p=0.001). Shortened OS following Flu treatment was observed among patients in 70-79 age group (HR=19.22, p=0.005), and in patients older than 80 years (HR=47.94; p<0.001). Similarly, shortened OS after Flu therapy was also found in patients who were older than 70 y.o and had either a higher total CIRS score (HR=4.73,p=0.025) or severe organ dysfunction (CIRS3+; HR=5.4, p=0.015). Interestingly, multivariate analysis including age, PS and CIRS, treatment with cyclophosphamide-based regimens (excluding FCR) was also predictive of shortened OS after therapy in patients with CIRS≥7 (HR=10.4, p=0.001), CIRS-3+ (HR=7.6, p=0.001) and total CIRS (HR=8.2, p=0.001). Notably, multivariate analysis with Chl- based regimens demonstrated improved OS for patients with CIRS≥7 (HR=0.175, p=0.019), CIRS3+ (HR=0.125, p=0.005) and overall high total CIRS (HR=0.142, p=0.006) Conclusion: In summary, CIRS is a valuable prognostic indicator that can be used to estimate OS and PFS in patients with CLL who have comorbidities, both alone and in combination with patient's age. Our data also suggest that patients above 70 years with high CIRS score may be poor Flu candidates, and tend to do better with Chl- based regimens. However, prospective studies are needed to validate CIRS effect on overall survival and to optimize treatment strategies in this high-risk population, including in a setting of novel "targeted" therapies. Disclosures No relevant conflicts of interest to declare.
Relapse after allogeneic stem cell transplant in unfavorable-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) portends a poor prognosis. We conducted a single-center phase I dose-escalation study with lenalidomide maintenance in high-risk MDS and AML patients after allogeneic transplantation. Sixteen patients enrolled in a “3 + 3” study design starting at lenalidomide 5 mg daily, increasing in increments of 5 mg up to 15 mg. Lenalidomide was given for 21 days of a 28-day cycle for a total of six cycles. Most common dose-limiting toxicities were lymphopenia, diarrhea, nausea, and neutropenia. Two patients had acute graft-versus-host disease (GVHD), and five patients developed chronic GVHD. The maximum tolerated dose was 10 mg, after dose-limiting toxicities were seen in the 15 mg group. Two dose-limiting toxicities were seen from development of acute GVHD and grade III diarrhea. Limitations of the study include time to initiation at 6 months post transplant, as many high-risk patients will have relapsed within this time frame before starting maintenance lenalidomide. Overall, lenalidomide was well tolerated with minimal GVHD and low rates of relapse rates, warranting further study.
Background: Patients (pts) with High-risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) often proceed to allogeneic hematopoietic stem cell transplant (alloHSCT) due to poorer outcomes. This is the only chance of cure; however, relapse rates after alloHSCT remain high and range between 25-50%. Maintenance approaches post-HSCT, such as hypomethylating agents or tyrosine kinase inhibitors, have been used to decrease the relapse rate with mixed results. Lenalidomide is known to augment T/NK cell activity/proliferation which lead us to hypothesize that it will enhance the Graft-versus-Leukemia (GvL) effect without increasing the incidence of acute Graft-versus-Host (GvH). This study evaluates the safety of Lenalidomide as maintenance in the post alloHSCT setting; secondary endpoints include 1-year relapse rate, disease free survival (DFS) and incidence of acute/chronic GvH. Background: Pts aged 18-65 with High Risk AML or MDS (defined as complex cytogenetics, IPSS-R ≥ 3, 2°AML or residual AML at time of alloHSCT) in complete remission 6-10 months status post alloHSCT were eligible. As a Phase I trial, pts were enrolled using a "3 + 3" design starting at 5 mg of Lenalidomide daily for 21 days of 28-day cycle for up to 6 months. The dose of Lenalidomide was increased by 5 mg to a maximum of 20 mg until Maximum Tolerated Dose (MTD) was determined by the incidence of Grade III-IV toxicities or Grade II-IV GvH. Pts received GvH prophylaxis and supportive care at the discretion of the treating physician. Results: From 2/2013 to 7/2017, 13 pts (9 male and 4 female) were enrolled; 8 had AML, 3 had MDS and 2 had MDS/AML. 2 pts received matched sibling HSCT and 11 pts received matched unrelated HSCT. Of note, 2 pts were enrolled after receiving donor lymphocyte infusion/stem cell infusion. Median age was 54 (34-64). Median follow-up from alloHSCT is 36 mo (10-59 mo). MTD not yet reached with no DLT at 15 mg. 6 pts completed treatment with 3 stopping due to AE, 1 due to physician discretion, 1 due to patient preference and 1 due to other reason. Toxicities were graded by CTCAE v4.0 with the most prevalent Grade ≥3 events being lymphopenia (30%), diarrhea (15%) and nausea, vomiting, cytopenias (8%); no Grade 5 events occurred. Grade 4 acute GI GvH occurred in 1 pt, however this was confounded by the discontinuation of GvH prophylaxis 2 weeks prior. No effect on chimerism was seen. 1 pt relapsed within 1 year of completing Lenalidomide therapy; 12 pts remain in remission to date, including the 2 that received donor lymphocyte infusion/ stem cell infusion. Conclusion: The use of Lenalidomide in the post alloHSCT setting appears to be well tolerated. In this very high-risk population with expected relapse rates as high as 50%, this study demonstrated a relatively low incidence of relapse as well as a relatively low incidence of acute or chronic GvHD. Further studies on a larger scale are warranted to confirm these findings.
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