Measurable Residual Disease Assessment and Allogeneic Transplantation as Consolidation Therapy in Adult Acute Lymphoblastic Leukemia in Colombia

IntroductionDetectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. The objective of the study was to assess disease-free survival (DFS) and overall survival (OS) of patients with ALL according with MRD status at the end of induction therapy in a Colombian population.Patients and MethodsWe assessed a retrospective cohort to compare DFS and OS in adults with de novo ALL according to MRD status at the end of induction chemotherapy, and the type of postinduction consolidation strategy used.ResultsA total of 165 adults with ALL were included in the MRD part of the study, 73 patients in the MRD-negative group and 92 in the MRD-positive group. Median DFS for the MRD-positive group was 11 months (95% confidence interval, 11.7-22.2) and was not reached for the MRD-negative group (P < .001). At 3 years, DFS was 18% and 55%, respectively (P < .001). The median OS for MRD-positive patients was 16 months (95% confidence interval, 8.8-23.15) and was not reached in the MRD-negative group. At 3 years, OS was 26% and 51% for the former and latter group, respectively. Among subjects who did not receive a transplant, median DFS was 21 months for MRD-negative patients and 9 months for MRD-positive patients (P < .001). The median DFS was not reached in either group, whereas 3-year DFS was 64% for MRD-negative and 70% for MRD-positive patients who underwent transplantation in first remission (P = .861).ConclusionMRD status at the end of induction is an independent prognostic factor for DFS and OS in adult ALL. Allogeneic transplantation in first remission could overcome the adverse prognostic impact of MRD.     

Daratumumab,Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR

BackgroundIn the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed.Patients and MethodsEligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m²) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression.ResultsOf 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)–negativity rates (10⁻⁵) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed.ConclusionAfter 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.     

Comparison of Overall Survival Between De Novo and Secondary Acute Lymphoblastic Leukemia Patients of Different Ages

PurposeTo compare the overall survival (OS) between de novo and secondary acute lymphoblastic leukemia (ALL) patients in different age groups after chemotherapy.Patients and MethodsData from 8305 ALL patients undergoing chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database during 1975 to 2015 were included in this study, of which 7454 (80.11%) were in the de novo ALL group, and 851 (19.89%) were in the secondary ALL (sALL) group. Propensity matching was used before comparison of OS between the two groups.ResultsFemale ALL patients had a lower risk of death than male (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.88-0.98; P < .01). The mortality of black patients was higher than in white patients (HR, 1.29; 95% CI, 1.18-1.42; P < .001). Patients aged 45-75 years (HR, 1.82; 95% CI, 1.72-1.94; P < .001) and ≥ 75 years (HR, 3.85; 95% CI, 3.52-4.23; P < .001) had a higher risk of death. Separated/divorced (HR, 1.21; 95% CI, 1.10-1.34; P < .001) and widowed (HR, 1.35; 95% CI, 1.21-1.51; P < .001) patients had a higher risk of death than single patients. sALL patients had a higher risk of death than de novo ALL patients (HR, 1.21; 95% CI, 1.12-1.30; P < .001). The mean age of the de novo ALL group was lower than in the sALL group (51.05 vs. 60.25; P < .001) after the propensity score was matched, and the 1-, 2-, 3-, 4-, and 5-year OS of the de novo ALL group were higher than that of the sALL group aged 18-75 years (P < .001).ConclusionThe survival rate of ALL decreased with increased age. Patients with sALL had poorer OS than de novo patients aged 18-75 years.     

The prognostic significance of minimal residual disease in adult Egyptian patients with precursor acute lymphoblastic leukemia

BackgroundMinimal residual disease (MRD) studies in adult acute lymphoblastic leukemia (ALL) give highly significant prognostic information superior to other standard criteria as age, gender and total leucocytic count (TLC) in distinguishing patients at high and low risk of relapse.ObjectivesWe aimed to determine the value of MRD monitoring by flowcytometry (FCM) in predicting outcome in adult Precursor ALL patients.Patients and methodsBone marrow (BM) samples were analyzed by 4-color FCM collected at diagnosis and after induction therapy (MRD1) to correlate MRD positivity with disease free survival (DFS) and overall survival (OS).ResultsStudy included 57 adult ALL patients (44 males and 13 females) with a median age of 22 years (18–49). DFS showed no significant difference with age, gender and initial TLC (p = 0.838, 0.888 and 0.743, respectively). Cumulative DFS at 2 years was 34% for B-lineage ALL (n: 35) and 57% for T-lineage ALL (n: 18) (p = 0.057). Cumulative DFS at 2 years was 7% for MRD1 positive (high risk, HR) versus 57% for MRD1 negative patients (Low risk, LR) (p < 0.001). Cumulative DFS at 2 years was 29% for HR patients (n: 26) versus 55% for LR (n: 27) according to GMALL classification (p = 0.064). Cumulative OS did not differ according to age, gender and TLC (p = 0.526, 0.594 and 0.513, respectively). Cumulative OS at 2 years was 36% for B ALL (n: 39) versus 77% for TALL (n: 18) (p = 0.016) and was 49% for Philadelphia chromosome (Ph) negative patients versus 0% for Ph-positive patients (p < 0.001). Regarding MRD1, OS at 2 years was 18% for MRD1 HR (n: 17) versus 65% for MRD1 LR (n: 38) (p < 0.001). OS was 35% for high-risk patients (n: 30) and 62% for low-risk patients (n: 27) classified according to GMALL risk stratification (p = 0.017).ConclusionMRD by FCM is a strong independent predictor of outcome in terms of DFS and OS and is a powerful informative parameter in guiding individual treatment in ALL patients.     

Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome‐positive acute lymphoblastic leukemia

Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative‐minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative‐MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < .001 for positive‐MRD with complete remission [CR] and hazard ratio, 6.13; P < .001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative‐MRD or positive‐MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = .140), unlike imatinib. Alternative strategies using new‐generation TKI for high‐risk patients are warranted to improve the outcomes after allogeneic HSCT.     

Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia – Long-term results of trial ALL-REZ BFM P95/96

PurposeThis blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).MethodsIncluded were 80 children and adolescents with first intermediate risk BM relapse of ALL recruited in trial ALL-REZ BFM P95/96. We assessed the prognostic value of minimal residual disease (MRD) after induction therapy quantified by PCR using leukaemia clone-specific T-cell receptor/immunoglobulin gene rearrangements.ResultsMolecular good responders (MRD < 10^?3, n = 46) had a probability of event-free survival (pEFS) at 10 years of 76% standard error (SE) ± 6% and a cumulative incidence of second relapse (CIR) at 10 years of 21% SE ± 6%; pEFS of molecular poor responders (MRD ? 10^?3, n = 34) at 10 years was 18% SE ± 7% and CIR 61% SE ± 9% (p < 0.001). Cox regression analysis revealed MRD after induction to be the strongest independent prognostic parameter with a 6.6-fold increased risk (95% confidence interval 3.3–13.5, p < 0.001) for molecular poor responders to suffer a subsequent adverse event compared to good responders.ConclusionIn patients with intermediate risk BM relapse of ALL, low MRD after induction is associated with an excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with insufficient response have an extremely poor prognosis. Therefore, in the subsequent trial ALL-REZ BFM 2002, MRD is used to allocate molecular good responders to conventional post-induction therapy and molecular poor responders to allogeneic HSCT.     

A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases

IntroductionWhether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear.Material and MethodsSeventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test.ResultsThe median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy.ConclusionsIn patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy.     

Day +100 Platelet Count Predicts Survival After Allogeneic Hematopoietic Stem-Cell Transplantation in Children With Hematologic Malignancies

IntroductionRecovery of platelet count by day 100 after hematopoietic stem-cell transplantation (HSCT) is affected by many factors and has been reported to be a predictor of overall survival (OS) in a variety of diseases and donor types. We investigated the correlation between day +100 platelet count and OS after allogeneic HSCT in a relatively homogeneous cohort of pediatric patients with hematologic malignancies.Patients and MethodsWe conducted a retrospective study of 152 consecutive patients who underwent allogeneic HSCT at the Children’s Cancer Hospital Egypt between 2009 and 2015 with a minimum follow-up duration of 1 year after transplantation. All eligible patients received myeloablative conditioning, and all had matched related donors. Patients who survived without relapse until day 100 after HSCT were divided into 2 groups: early platelet recovery (EPR; platelet count ≥ 100 × 10⁹/L at day +100 after transplantation) and delayed platelet recovery (DPR; platelet count < 100 × 10⁹/L at day +100 after transplantation).ResultsAt day +100, 113 patients (74%) had EPR and 39 patients (26%) had DPR. With a median follow-up of 41 months (range, 12-93 months), 41 patients (27.2%) died, 35 of relapsed disease. The 3-year disease-free survival (DFS) and OS were 68 ± 7.84% and 71.9 ± 7.84%, respectively. The 3-year OS was 77.9% in the EPR group and 57.1% in the DPR group (P = .006). Three-year DFS of the EPR and DPR groups were 73.2 ± 9% and 54.8 ± 16.3%, respectively (P = .02). Incidence of disease relapse for EPR and DPR patients was 22.6% and 39.5%, respectively (P = .04). Multivariate analysis for survival identified DPR as a predictor of decreased survival (P = .002).ConclusionPatients with a robust platelet count at day 100 are likely to do well. However, patients who do not experience a platelet count of ≥ 100 × 10⁹/L have inferior long-term OS and DFS and may require further evaluation at the day 100 time point.     

Timing of Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Current Therapies

BackgroundAutologous stem cell transplantation (SCT) during the initial treatment of multiple myeloma has been shown to improve progression-free survival (PFS) but not overall survival (OS). While awaiting further prospective data, we retrospectively analyzed the outcomes of patients at our program.Patients and MethodsWe included consecutive patients with newly diagnosed myeloma who had undergone stem cell harvest (SCH) from 2005 to 2014 and separated them into early (SCT within 12 months of diagnosis) and delayed (all others, including SCT not yet) groups. The outcomes were OS, PFS to first relapse, and PFS to second relapse.ResultsOf the 514 patients who had undergone SCH, 227 were in the early and 287 in the delayed groups. Patients in the delayed group who had undergone SCT had received more therapy before SCT (55% had received ≥ 2 lines vs. 6% in the early group; P < .001), had had more progressive disease at SCT (34% vs. 4%; P < .001), had received melphalan doses < 200 mg/m² (22% vs. 10%; P = .001), and had had lower rates of very good partial response or better after SCT (58% vs. 79%; P = .001). On multivariable analysis, no differences were found in median OS (90 vs. 84 months; P = .093), PFS to first relapse (40 vs. 37 months; P = .552), or PFS to second relapse (54 vs. 52 months; P = .488) between the early and delayed groups.ConclusionDelaying SCT did not affect OS or even PFS to second relapse in our cohort of patients with newly diagnosed myeloma who had received current era induction therapy.     

Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation

BackgroundMost patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required.Patients and methodsWe retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR).ResultsNGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRD^NGS(−)] (defined as <10⁻⁶) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years,P < 0.001) and overall survival (OS) (100% at 4 years,P =0.04) than MRD^NGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRD^NGS(−) (n = 24) showed a significantly better PFS than those that were MRD^NGS(+) (n = 15) (P =0.02). Moreover, MRD^NGS(−) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRD^NGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10⁻⁷) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33).ConclusionsLow level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.     

Minimal Residual Disease and Survival Outcomes in Patients With Chronic Lymphocytic Leukemia: A Systematic Review and Meta-analysis

BackgroundPatients with chronic lymphocytic leukemia (CLL) who achieve undetectable minimal residual disease (U-MRD) (ie, < 10^-4 detectable leukemic cells in peripheral blood or bone marrow) have better outcomes than those with detectable MRD. To assess the magnitude of improvement of progression-free survival (PFS) or overall survival (OS) in patients who achieved U-MRD after upfront chemotherapy (CT) or chemo-immunotherapy (CIT), we conducted a systematic review and meta-analysis.Materials and MethodsThe screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility.ResultsEleven studies comprising 2457 patients with CLL treated in upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Nine studies (n = 2088) provided data on the impact of MRD on PFS and 6 (n = 1234) on OS. MRD was the main endpoint in only 2 of these studies (n = 213). Tests of heterogeneity revealed significant differences among studies for PFS and OS, which highlights differences across studies. U-MRD status was associated with significantly better PFS overall (P < .001) and in patients who achieved conventional complete remission (P = .01). Regarding OS, U-MRD predicted longer OS globally (P < .001) but not in patients having achieved complete remission (P = .82).ConclusionsU-MRD status after treatment with CT or CIT in newly diagnosed CLL is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of CLL.     

The Lymphoma-Associated Macrophage to Hodgkin-Reed-Sternberg Cell Ratio Is a Poor Prognostic Factor in Classic Hodgkin Lymphoma Patients

BackgroundDespite the relatively high rate of curability, approximately 20% to 30% of patients with classic Hodgkin lymphoma relapse. Hodgkin-Reed-Sternberg (HRS) cells:lymphoma-associated macrophages (LAMs) cross talk promotes tumor growth and resistance to therapy. The aim of the study was to assess the prognostic role of the LAM to HRS ratio (LHR) in lymph node biopsies using a novel automated system for scanning large sample areas.Patients and MethodsHigh-quality tissue samples obtained from 71 patients and stained with anti-CD30 and anti-CD68 were analyzed using the TissueFAXS (TissueGnostics).ResultsA high LHR was associated with inferior 5-year progression-free survival (PFS; 50.0% vs. 79.3%; P = .032) and overall survival (OS; 65.4% vs. 92.3%; P = .012). Multivariate Cox regression identified the high LHR as an unfavorable prognostic factor for PFS (hazard ratio [HR], 3.07; P = .029) and OS (HR, 4.56; P = .025).ConclusionA high LHR at diagnosis is associated with a higher risk of lymphoma progression or death. Automated image analysis is a new tool that can overcome technical limitations of by microarray samples in lymphomas with high intratumor heterogeneity.     

Increased Bone Marrow Plasma-Cell Percentage Predicts Outcomes in Newly Diagnosed Multiple Myeloma Patients

BackgroundPrevious reports have suggested that a higher bone marrow plasma-cell percentage (BMPC%) is associated with worse outcomes. However, it is unknown whether BMPC% is an independent predictor because genetic information was not available at that time. Currently the impact of BMPC% at diagnosis of multiple myeloma (MM) is not well described.Patients and MethodsWe evaluated the prognostic impact of BMPC% ≥ 60% versus < 60% in 1426 newly diagnosed MM patients. All patients had an estimation of their BMPC% at diagnosis, and the highest percentage was used. Progression-free survival (PFS) and overall survival (OS) analyses were performed by the Kaplan-Meier method. Univariate and multivariate analyses for PFS and OS using the Cox proportional hazards model were performed for age, Revised International Staging System (R-ISS) score, creatinine level, and BMPC%.ResultsBMPC% ≥ 60% was found in 562 patients (39%), and the median PFS was shorter for these patients compared to BMPC% < 60% (22.6 vs. 32.1 months; P < .0001). Also, for OS, the median was shorter for the higher BMPC% group (53.4 vs. 75.4 months; P < .0001). On the multivariate analysis for PFS, age ≥ 65 years (hazard ratio [HR], 1.46; P < .0001), R-ISS (1-2 vs. 3) (HR, 0.49; P < .0001), and BMPC% ≥ 60% (HR, 1.23; P = .015) were predictive. On the multivariate analysis for OS, age ≥ 65 years (HR, 2.23; P < .001), R-ISS (1-2 vs. 3) (HR, 0.41; P < .0001), and BMPC% ≥ 60% (HR, 1.24; P = .02) were also predictive.ConclusionBMPC% ≥ 60% at diagnosis is predictive for PFS and OS, even in a multivariate analysis that included known prognostic factors for MM.     

Peripheral Blood Lymphocyte-to-Monocyte Ratio at Relapse Predicts Outcome for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in the Rituximab Era

BackgroundPatients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis, even in the rituximab era. Several studies have reported the clinical importance of the peripheral blood lymphocyte-to-monocyte ratio (LMR) in various malignancies, including lymphoma. However, the prognostic value of the LMR in relapsed/refractory DLBCL has not been well evaluated. The purpose of the present study was to investigate whether the LMR at relapse can predict clinical outcomes for relapsed/refractory DLBCL patients treated with rituximab.Patients and MethodsWe analyzed data on 74 patients with relapsed/refractory DLBCL, who were initially treated with R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone) or an R–CHOP-like regimen.ResultsThere was a significant association between a low LMR (≤ 2.6) and shorter overall survival (OS; P < .001) and progression-free survival (PFS; P < .001) compared with the high LMR group (> 2.6). Multivariate analysis showed that LMR was an independent prognostic factor for OS (P < .001) and PFS (P < .001), as was the international prognostic index (IPI) at relapse for OS. In addition, the LMR had an incremental value for OS and PFS compared with the IPI at relapse.ConclusionThe LMR predicts OS and PFS outcomes in relapsed/refractory DLBCL patients treated with rituximab, and might facilitate better stratification among patients in low- and intermediate-risk IPI groups.     

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

BackgroundRapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population.Materials and MethodsArchival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS).ResultsFifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005).ConclusionsA low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.     

Propensity-score Matched Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia

BackgroundRelapsed/refractory acute myeloid leukemia (AML) confers a poor prognosis, and there is no single standard of care first-line salvage regimen. FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) is a common salvage regimen with a favorable toxicity and efficacy profile in poor-risk AML.Materials and MethodsWe conducted a single-center, retrospective analysis of first relapse/primary refractory patients with AML that received salvage chemotherapy from January 2009 to July 2019. We propensity-score matched patients 1:1 (based on age at diagnosis, cytogenetic risk group, Charlson comorbidity index, de novo vs. secondary AML, and whether or not they received an allogeneic stem cell transplant in first complete remission) into 2 groups, FLAG (Group 1) or non-FLAG (Group 2) as first-line salvage regimen, with 66 patients in each group. The primary endpoint was overall response rate (complete response and complete response with incomplete hematologic recovery).ResultsThe median patient age was 59 years (range, 19-80 years). Patients treated with FLAG had a higher overall response rate (complete response/complete response with incomplete hematologic recovery) (71.2% vs. 50.0%; odds ratio, 2.47; 95% confidence interval [CI], 1.21-5.08; P = .013), longer event-free survival (8.9 vs. 2.1 months; hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P = .005), and longer overall survival (14.2 vs. 5.9 months; HR, 0.62; 95% CI, 0.41-0.93; P = .019). Patients who received FLAG had a shorter median duration of neutropenia (22 vs. 34 days; HR, 0.43; 95% CI, 0.29-0.64; P < .001).ConclusionThis analysis supports the FLAG regimen as an effective and well-tolerated salvage therapy for patients with relapsed/refractory AML.     

Cyclophosphamide,Bortezomib and Dexamethasone (CyBorD) for the Treatment of Newly Diagnosed AL Amyloidosis: Impact of Response on Survival Outcomes

BackgroundCyBorD (cyclophosphamide, bortezomib, and dexamethasone) is an effective regimen for the treatment of patients with newly diagnosed immunoglobulin light chain (AL) amyloidosis. CyBorD can induce rapid hematologic responses (HRs). However, it remains inadequate to enhance outcomes in high-risk groups. In addition, minimal information is available on the impact of minimal residual disease (MRD) in overall survival.Patients and MethodsAll consecutive patients with newly diagnosed AL amyloidosis treated with CyBorD from January 2012 to August 2018 were evaluated. HR and organ response was assessed as per standard guidelines. Further, MRD was evaluated by multiparameter flow cytometry in patients with confirmed complete response (CR).ResultsAfter a median of 4 cycles, HR was seen in 31 (91.2%) cases, including CR in 9 (26.5%), very good partial response in 9 (26.5%), and partial response in 13 patients (38.2%). Organ response at 6 months was documented in 11 (32.4%) cases. With respect to cardiac response, a > 30% decrease of NT-proBNP was observed in 4 (19%) of 21 evaluable cases (NTproBNP > 650 ng/L) at a median of 6 months. The median progression-free survival was 26.7 months. Patients who achieved CR exhibited a better overall survival compared with those without CR (P = .001). No difference on overall or progression-free survival among cases achieving CR irrespective of their MRD status was observed (P > .05).ConclusionsIn summary, CyBorD showed a ≥ very good partial response rate of 53% with 26.5% achieving CR, which is similar to that seen in previous studies. In addition, MRD negativity assessed by multiparameter flow cytometry in patients with CR resulted in no difference on survival outcomes.     

Minimal Residual Disease Negativity Does Not Overcome Poor Prognosis in High-Risk Multiple Myeloma: A Single-Center Retrospective Study

BackgroundMinimal residual disease (MRD) is a standard measurement for response assessment in multiple myeloma (MM). Despite new treatments, high-risk MM patients continue to have poor prognosis. We evaluated the effect of MRD negativity in high-risk versus standard-risk patients.Patients and MethodsWe retrospectively evaluated all consecutive MM patients who underwent routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10⁻⁵ at our center from 2015 to 2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups.ResultsOne hundred thirty-six patients with MRD testing after initial therapy or autologous stem-cell transplantation were identified. At a median follow-up of 14 months (range, 1-36 months), progression-free survival and overall survival were significantly worse in high-risk versus standard-risk patients. During the study period, 50% of high-risk group had experienced disease progression (relapse and/or death) versus 20% in the standard-risk group (P = .0006). No patients with standard-risk died, but 4 (14%) in the high-risk group did (P = .0007). Regardless of MRD status, high-risk patients had statistically significant worse progression-free survival than standard-risk patients. At median follow-up, those with disease 10% standard-risk/MRD negative; 20% standard-risk/MRD positive; 40% high-risk/MRD negative; and 45% high-risk/MRD positive had either experienced relapse or died (P = .0041). MRD status did not significantly affect overall survival in either group (P = .0914); however, longer follow-up is needed to assess survival.ConclusionGenetic abnormalities remain a powerful prognostic indicator for MM, regardless of MRD status. For newly diagnosed MM patients treated with novel triple-drug initial therapy and frontline autologous stem-cell transplantation, MRD-negative status did not mitigate the poor-prognosis outcomes of high-risk MM patients.     

Factors affecting the outcome of patients with metastatic leiomyosarcoma treated with doxorubicin-containing chemotherapy

BackgroundTo determine whether pulmonary metastasectomy or the addition of ifosfamide/dacarbazine to a doxorubicin-containing regimen offers a survival benefit to adult patients with metastatic leiomyosarcoma.Patients and methodsWe retrospectively collected data from 147 patients treated with a doxorubicin-containing regimen from 1998 to 2008.ResultsProgression-free survival (PFS) was 6.5 months (range 1–141 months). We did not identify an independent prognostic factor for PFS. Planned dose of doxorubicin was the sole parameter improving PFS [hazard ratio (HR) = 0.13, P = 0.023]. Overall survival (OS) was 17 months (range 1–115 months). The sole identified prognostic factor for OS was the interval between initial diagnosis and metastatic relapse. After adjustment to this prognostic factor, metastasectomy improved OS (HR = 0.52, P = 0.012) and the addition of ifosfamide seemed to worsen OS (HR = 1.42, P = 0.028).ConclusionIn our analysis, combined regimens did not improve the outcome. Maintenance of the doxorubicin dose was associated with improved PFS. Metastasectomy favorably influenced OS.     

Ofatumumab,Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation

BackgroundMore than one-half of high-risk patients with relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) relapse after autologous hematopoietic cell transplantation (auto-HCT). In this phase II study, we investigate the long-term outcomes of high-risk patients with rrDLBCL receiving intensive consolidation therapy (ICT) with OVA (ofatumumab, etoposide, and high-dose cytarabine) prior to auto-HCT.Patients and MethodsThe primary endpoints were the ability of OVA to mobilize peripheral stem cells and the 2-year progression-free survival (PFS) rate following OVA. Secondary endpoints included safety, 2-year overall survival (OS), impact of cell of origin (COO), and the prognostic utility of next-generation sequencing minimal residual disease (MRD) testing. We simultaneously retrospectively assessed the outcomes of DLBCL patients who underwent ICT with a similar regimen at our institution.ResultsTwenty-seven patients received salvage chemotherapy, with a response rate of 25% in patients with germinal center B-cell (GCB)-DLBCL versus 92% in patients with non-GCB-DLBCL (P = .003). Nineteen responding patients underwent ICT with OVA (100% successful stem cell mobilization). The 2-year PFS and OS rate was 47% and 59%, respectively, with no difference based on COO. Similar findings were observed when the study and retrospective cohorts were combined. Neutropenia was the most common toxicity (47%). MRD-negative patients at the completion of salvage had a median OS of not reached versus 3.5 months in MRD-positive patients (P = .02).ConclusionsOVA followed by auto-HCT is effective and safe for high-risk rrDLBCL. Patients with GCB-DLBCL had a lower response to salvage chemotherapy, but no difference in outcomes based on COO was seen after auto-HCT. MRD testing in the relapsed setting was predictive of long-term survival.