Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.Subject terms: Translational research, Disease-free survival     

Single Center Experience of Autologous Stem Cell Transplantation in Patients with Systemic Light Chain Amyloidosis in Korea

BackgroundSystemic light chains is the most common systemic amyloidosis. In patients with AL amyloidosis, the prognosis is influenced by the extent of organ damage, especially cardiac involvement. Autologous stem cell transplantation (ASCT) is a highly effective treatment for AL amyloidosis for selective patientMethodsOne hundred patients treated with ASCT for AL amyloidosis were reviewed in the Samsung Medical Center amyloidosis cohort. The cardiac, renal, and hematologic response was analyzed, and survival results compared based on organ involvement and hematologic response.ResultsThe most common involved organ was kidney (n = 62) followed by heart (n = 50). The organ response rate was 44.0% and 37.1% in the patients with cardiac and renal involvement, respectively. In hematologic response, overall response rate (ORR) was 79.0%, including 48.0% complete response (CR). Median overall survival (OS) in patients with and without hematologic CR were not reached and 64.2 months (95% CI, 19.5 to 109.0), respectively (P < .001). The survival rate was not significantly different between patients with or without cardiac or renal involvement. Treatment-related mortality (TRM) in 30 days and 100 days was 2.0% and 3.0%, respectively.ConclusionsASCT is an effective treatment option for eligible patients with AL amyloidosis. Achieving hematologic CR is essential for long-term survival.     

Light Chain Amyloidosis (AL) Associated With B Cell Lymphoma a Single Center Experience

IntroductionLight chain (AL) amyloidosis and B‐cell lymphoma represent 5% to 7% of all AL, Systemic amyloidosis, deposits in sites remote from the underlying lymphoma, and peritumoral amyloidosis deposition is within the immediate vicinity.Materials and MethodsWe conducted a retrospectively study to identify and describe AL with B cell lymphoma at Princess Margaret Cancer Center from 01 January 1997 to 31 July 2019.ResultsThirty-five patients with AL and lymphoma, an incidence of 6, 2%, median age of diagnosis of 66 (range 47 to 86), majority male, most had underlying Waldestrom's Macroglobulinemia. 21 patients with peritumoral AL (PAL), and 15 with systemic AL. 42.8% of the patients had major organ involvement. 35% got treatment with Rituximab with alkylator, 20% received proteasome inhibitors, 17% patients were on a watch and wait approach, amyloid response showed very good partial response > 45.8%, and lymphoma ORR was 42.8%, with a median follow up of 31.5 months. A 36 month overall survival (OS) and progression-free survival (PFS) showed worse outcomes for heart involvement OS (P = .002), PFS (0.057) and IgM subtype OS (P = .02), PFS (0.01).ConclusionWe have shown adverse outcome with IgM AL and to document a differences in OS and PFS not previously reported for PAL.     

Oral cyclic melphalan and dexamethasone for patients with AL amyloidosis

PurposeAggressive treatment of amyloid light chain (AL) amyloidosis with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT because of amyloid-associated organ dysfunction.Patients and MethodsWe report on 70 patients with AL amyloidosis treated with oral cyclic melphalan and dexamethasone.ResultsOf 48 evaluable patients who survived and returned for follow-up assessment, 6 patients (13%) achieved a complete hematologic response and 12 patients (25%) a partial hematologic response. Responses were non-inferior for patients receiving weekly “low-dose” dexamethasone compared with those receiving 4 day pulses. Median survival for the 70 patients has not yet been reached with a median follow-up of 17 months. Nineteen patients (27%) received additional treatment leading to improvement in survival.ConclusionMelphalan/dexamethasone can lead to hematologic responses and improvement in survival, particularly for those who can receive additional treatment for AL amyloidosis.     

Clinical Analysis of Cardiac Involvement in 53 Patients With Multiple Myeloma Coexistent With Light Chain Amyloidosis

BackgroundWe identified 53 patients with multiple myeloma (MM) who had biopsy evidence of light chain amyloidosis (AL), and studied their cardiac involvement and outcomes.Patients and MethodsOur cohort consisted of 53 patients in whom MM and AL were initially diagnosed from July 1, 2006 to June 30, 2016.The diagnosis of MM required > 10% of clonal plasma cells in bone marrow and 1 of the CRAB symptoms, meanwhile, the diagnosis of AL must meet pathologic diagnostic criteria and monoclonal immunoglobulin light chain. Echocardiograms and cardiac biomarker such as N terminal pro B-type natriuretic peptide was used for evaluation of cardiac damage on the baseline and before every cycle of the regimen.ResultsThere were 36 men and 17 women with a median age of 59 years; their main organ involvement was kidney (72%) and heart (62%). Of these, 22 patients were treated with a bortezomib-based regimen, and the response rate was more effective than the other 21 patients who received non-bortezomib-based regimens (64% vs. 29%). The median overall survival (OS) for the total cohort was 12 months (P < .05). The median OS of the MM cohort with International Staging System stage I and II together was 34 months, which was longer than that of patients with stage III of 8 months. The median OS in Mayo stages I, II, and III was 38, 8, and 1 months, respectively (P < .05). Cardiac involvement significantly adversely affected survival (6 vs. 40 months), as did systolic blood pressure (< 90 mmHg, 3 vs. 8.5 months).ConclusionsPatients coexistent with MM and AL is rare; AL has a negative impact on survival for the total cohort. Especially, cardiovascular dysfunction caused by AL maybe a major determinant of shortening survival.     

A comparative study of cyclophosphamide,thalidomide and dexamethasone (CTD) versus bortezomib and dexamethasone (BDex) in light-chain amyloidosis

BackgroundCyclophosphamide, thalidomide, and dexamethasone (CTD) or bortezomib and dexamethasone (BDex) show substantial efficacy in patients with amyloid light-chain (AL) amyloidosis, especially in Chinese patients. Currently, both regimens are recommended as primary treatment options for AL amyloidosis, but no comparative study has been reported.MethodsWe retrospectively evaluated the outcomes of 81 AL patients who received CTD (n = 42) or BDex (n = 39) and used Mayo stage 2012 to match 26 pairs of patients.ResultsIn the whole cohort, the overall hematologic responses were 86% vs 91% in the CTD and BDex groups, including a complete response of 56% vs 71% based on an intention-to-treat (ITT) analysis. One- and 2-year overall survival (OS) was 90.2% and 81.7% with CTD, and 87.6% and 82.7% with BDex. After matching, BDex regimen induced a significantly deeper and more rapid hematologic response over CTD, but no statistically significant difference in OS (ITT analysis, P = 0.24; 6-month landmark analysis, P = 0.48). Cardiac response rates were similar, while there was a trend for higher renal responses in patients treated with BDex (68% vs 44%, P = 0.09). Additionally, BDex was associated with significantly improved survival in patients with advanced disease (Mayo stage III or worse; P = 0.009). Patients treated with BDex reported more episodes of severe hematologic toxicity and diarrhea.ConclusionsCTD and BDex are effective treatments for Chinese patients with AL amyloidosis, but BDex regimen appears superior to CTD in achieving a more rapid and deeper clonal response, and in improving OS in patients with advanced disease.     

Autologous Hematopoietic Cell Transplantation Versus Chemotherapy Alone for Immunoglobulin Light Chain Amyloidosis: A Retrospective Study

IntroductionImmunoglobulin light chain (AL) amyloidosis is caused by the deposition of monoclonal immunoglobulin light chains, for which autologous hematopoietic cell transplantation (AHCT) is one of the most effective therapies. In small studies comparing AHCT with chemotherapy alone, AHCT was associated with better survival.Patients and MethodsIn this study, we compared the outcomes of AHCT with those of chemotherapy alone in 232 patients. We retrospectively reviewed the outcomes in 74 patients who underwent AHCT with those of 158 patients treated only with chemotherapy.ResultsThe median event-free survival (EFS) (73 vs. 9 months; P < .001) and overall survival (OS) (not achieved vs. 39 months; P < .001) were superior in the AHCT group versus those in the chemotherapy group. On multivariate analysis, AHCT was significantly associated with better EFS (hazard ratio, 0.410; 95% confidence interval, 0.241-0.697; P = .0010) and OS (hazard ratio, 0.313; 95% confidence interval, 0.155-0.636; P = .0013) than chemotherapy alone. Even when patients with severe findings (mean left ventricular thickness > 12 mm, brain natriuretic peptide level > 400 pg/mL, and creatinine level > 2.0 mg/dL) and elderly patients (age > 65 years) were excluded, both EFS and OS were significantly better in the AHCT group than in the chemotherapy group upon univariate and multivariate analyses.ConclusionAHCT yielded better EFS and OS than chemotherapy alone in patients with AL amyloidosis. AHCT should be considered for eligible patients.     

Clinical Characteristics and Outcome of Primary Systemic Light-Chain Amyloidosis in Greece

Background:Primary systemic light-chain (AL) amyloidosis is characterized by the deposition of immunoglobulin light chain–derived amyloid fibrils in various tissues leading to multiorgan dysfunction.Patients and Methods:In order to define characteristics, treatment, and outcome of Greek patients with AL amyloidosis, we analyzed 112 unselected patients with AL from several hospitals.Results:The heart was involved in 59% of patients and kidneys in 71%. Patients were treated with several different treatment regimens; high-dose dexamethasone-based regimens were used as primary treatment in 43% and melphalan-based regimens in 37%, while 12% received up-front bortezomib with dexamethasone. A hematologic response to first-line therapy was documented in 50% (complete response, 14.5%), and organ responses were observed in 25% of patients, the latter being strongly associated with achievement of hematologic response. Median overall survival was 34.2 months and was independently affected by heart involvement, creatinine, age, involvement of ≥ 2 organs, and bone marrow plasmacytosis > 30%. In patients with cardiac involvement, advanced age and extended bone marrow plasmacytosis were associated with an even worse outcome, while for patients without heart involvement, only bone marrow plasmacytosis was independently associated with survival. Hematologic response was associated with improved survival in patients with heart involvement but mostly in patients with less bone marrow infiltration.Conclusion:In this first series of patients from Greece with AL amyloidosis, disease features and outcome appeared similar to those reported from tertiary centers. Heart involvement and bone marrow plasma cell infiltration comprise adverse prognostic factors but also indicate the heterogeneity of the disease and the need for individual treatment approaches.     

Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p < 0.005). At 1-month, patients with CR and iFLC < 20 mg/l had a significantly better survival compared to CR and iFLC > 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.Subject terms: Myeloma, Prognosis     

Adding Cyclophosphamide to Bortezomib and Dexamethasone was not Associated With Improved Outcomes of Patients With Newly Diagnosed Light Chain Amyloidosis: A Retrospective Study

IntroductionBefore 2021, the combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was one of the most used upfront therapy for systemic immunoglobulin light chain (AL) amyloidosis. Recently, daratumumab in combination with VCd resulted in improved outcomes compared to VCd. However, it's still unclear the role of cyclophosphamide in this combination.Materials and MethodsWe conducted this retrospective single-institutional study to compare the outcomes of upfront bortezomib and dexamethasone with or without cyclophosphamide (VD vs. VCd).ResultsOf 136 total patients, 62 received VD and 74 received VCd. The median age was 64 and the median number of organs involved was 2. Hematologic response was achieved among 73.4% patients in the VD arm and 85.9% in the VCd arm at 3 months (P = .15). Best organ response was not different between 2 arms (34.1% vs. 52.9% for VD and VCd arms, respectively; P = .28). After a median follow-up of 24.4 months, 2-year OS for VD and VCd arm was 70.6% and 84.6% respectively. The median overall survival was 70 months for VD arm and not reached for VCd arm (P = .30). There was no statistically significant difference in median time to next therapy (9.3 vs. 13.5 months for VD and VCd arms, respectively. P = .99).Conclusionthe addition of cyclophosphamide to VD was not associated with improved outcomes of patients with AL amyloidosis in this retrospective study.     

Real world outcomes with Bortezomib Thalidomide dexamethasone and Cyclophosphamide Bortezomib dexamethasone induction treatment for transplant eligible multiple myeloma patients in a Latin American country. A Retrospective Cohort Study from Grupo Argentino de Mieloma Múltiple

Data about treatment outcomes and toxicity in Latin America are scarce. There are differences with central countries based on access to healthcare system and socioeconomic status. Argentinean Society of Hematology recommends bortezomib-based triplets for induction treatment of transplant eligible newly diagnosed multiple myeloma patients. Most common options are CyBorD (cyclophosphamide, bortezomib and dexamethasone) and VTD (bortezomib, thalidomide and dexamethasone). Main goal of our retrospective, multicentric study was to compare very good partial response rate (VGPR) or better after induction treatment in a real-world setting in Argentina. Secondary objectives included comparison of complete response (CR) post-induction and after bone marrow transplantation, grade 3-4 adverse events (AEs), progression-free survival (PFS) and overall survival (OS). Three hundred twenty-two patients were included (median age at diagnosis: 57 years; 52% male; 28% had ISS3; 14% with high-risk cytogenetics; median follow up: 34 months). CyBorD was indicated in 74% and 26% received VTD. In VTD arm, 72.62% of patients achieved at least VGPR vs 53.36% receiving CyBorD (odds ratio, OR: 1.96 [95% confidence interval, CI: 1.08-3.57; P = .026] after adjusting by age, ISS [International Staging System], lactate dehydrogenase levels (LDH) and cytogenetic risk. Difference in VGPR was 19.26% (95% CI: 15-24). CR rate were 35.92% (VTD) vs 22.55% (CyBorD) (adjusted OR: 2.13 [95% CI: 1.12-4.05]). Difference in CR was 13.37% (95% CI: 9.6-17.53). Adverse events (AEs) were more common with VTD (69.05% vs 55.46% for CyBorD; P = .030), especially grade 3-4 neuropathy (P = .005) and thrombosis (P = .001). Thromboprophylaxis was inadequate in 20.24% of patients. Hematological AEs were more common with CyBorD, especially thrombocytopenia (P = .017). PFS and OS at 24 months were not different between treatments. In this real-world setting, VTD was associated with better CR and VGPR than CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina, based on safety profile. Frontline autologous stem cell transplantation improves quality of responses, especially in countries with limited access to new drugs.     

Outcomes of renal transplantation in patients with AL amyloidosis: an international collaboration through The International Kidney and Monoclonal Gammopathy Research Group

Effective systemic therapies suppress toxic light chain production leading to an increased proportion of patients with light chain (AL) amyloidosis who survive longer albeit with end-stage renal disease. There is a critical need to identify patients in this population who benefit from renal transplantation. This multicenter, observational study from five countries includes 237 patients with AL amyloidosis who underwent renal transplantation between 1987 and 2020. With a median follow-up of 8.5 years, the median overall survival from renal transplantation was 8.6 years and was significantly longer in patients with complete and very good partial hematologic responses (CR + VGPR) compared to less than VGPR (9 versus 6.8 years; HR: 1.5, P = 0.04 [95% CI: 1–2.1]) at renal transplantation. Median graft survival was 7.8 years and was better in the CR + VGPR group (8.3 vs 5.7 years, HR: 1.4, P = 0.05 [95% CI: 1–2]). The frequency and time to amyloid recurrence in the graft was also lower (16% vs 37%, p = 0.01) and longer (median time not achieved vs 10 years, p = 0.001) in the CR + VGPR group. Comparing CR vs. VGPR there was no difference in overall or graft survival. Although 69 patients (29%) experienced hematologic relapse, treatment effectively prevented graft loss in the majority (87%). Renal transplantation in selected AL amyloidosis patients is associated with extended overall and renal graft survival. Patients with hematologic CR or VGPR have the most favorable outcomes, and these patients should be considered for renal transplantation.Subject terms: Haematological cancer, Medical research     

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.     

Efficacy and Safety of Blinatumomab for the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: A Systemic Review and Meta-Analysis

ObjectiveThe aim was to evaluate the efficacy and safety of blinatumomab monotherapy for the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL).MethodsPubMed, Embase, Web of Science, and Cochrane Library were searched to collect clinical studies related to blinatumomab. The primary outcome measures were complete remission (CR), and minimal residual disease (MRD) response. Prognostic indicators included overall survival (OS) and relapse-free survival time (RFS). Grade ≥3 adverse reactions were mainly analyzed for safety, including cytokine release syndrome (CRS), neurological events and hematological toxicity. The heterogeneity was quantified by I² statistic, which reflected the proportion of the true heterogeneity to the variance of the total effect size. Studies were considered heterogeneous if the I² statistic was greater than 50%, and conversely, studies were homogeneous.ResultsA total of 18 studies involving 1,373 patients were included. The analysis results showed a CR rate of 54% (95%CI:44%-64%) and an MRD response rate of 43% (95%CI:34%-51%). The CR rate was higher in patients with bone marrow (BM) blast <50% than in patients with BM blast ≥50% (71% vs. 34%). The median OS and RFS were 8.16 months (95%CI:6.64-9.69) and 6.02 months (95%CI:4.63-7.41), respectively. For safety analysis, the incidence of grade ≥3 adverse events (AEs) was 80% (95%CI:72%-88%), the incidence of grade ≥3 neurological toxicity was 7% (95%CI:4%-11%), and the incidence of grade ≥3 CRS was 3% (95%CI:2%-5%). However, the mixture of retrospective and prospective studies led to heterogeneity to some extent in this meta-analysis.ConclusionBlinatumomab is effective in the treatment of R/R B-ALL with a controlled occurrence of AEs and a reliable safety profile.     

Minimal residual disease-based effect and long-term outcome of first-line dasatinib combined with chemotherapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia

BackgroundThe use of imatinib combined with chemotherapy has demonstrated improved outcome in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, a substantial proportion of patients continue to die as a result of disease progression.Patients and methodsWe assessed the minimal residual disease (MRD)-based effect and long-term outcome of first-line incorporation of dasatinib (100 mg once daily) into chemotherapy alternatively for adults with Ph-positive ALL. The primary end point was the major molecular response (MMR) rate by the end of the second dasatinib cycle. Patients with a donor proceeded to allogeneic stem cell transplantation (SCT) as early as possible. MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction (4.5-log sensitivity) using bone marrow samples.ResultsFifty-one patients (median age, 46 years) were enrolled and treated with this strategy. After the first dasatinib cycle, 50 patients (98.0%) achieved complete remission (CR). By the end of the second dasatinib cycle, 46 (93.9%) of 49 assessable patients had persistent CR, and 38 (77.6%) had MMR (32.7%) or undetectable MRD (44.9%). On the basis of the MRD kinetics by this time point, the numbers of early-stable, late, and poor molecular responders were 23 (46.9%), 15 (30.7%), and 11 (22.4%), respectively. Thirty-nine patients (76.5%) underwent allogeneic SCT in CR1. After a median follow-up of 54 months, the 4-year cumulative incidence of relapse and disease-free survival (DFS) rate for all patients were 30.0% and 52.0%, respectively, and the corresponding outcomes among those receiving allogeneic SCT in CR1 were 20.5% and 64.1%, respectively. Poor molecular responders had a higher risk of relapse and DFS than those of early-stable molecular responders.ConclusionThis dasatinib-based protocol was effective for achieving a good quality molecular response and durable DFS in adults with Ph-positive ALL.Trial registrationclinicaltrials.gov, NCT01004497.     

Safety and Efficacy of Triplet Regimens in Newly Diagnosed Light Chain Amyloidosis

BackgroundThe prognosis of patients with systemic light chain (AL) amyloidosis, particularly cardiac, is poor. Treatments have been derived from multiple myeloma, but there are few studies that use triplet regimens in AL amyloidosis because of concern of greater toxicity than seen in myeloma.Patients and MethodsWe conducted a retrospective review of patients with newly diagnosed AL amyloidosis who were initially treated with a triplet regimen.ResultsFor the 9 patients included, the median age was 64 years, and 8 were ineligible for stem cell transplantation. At least 2 organs were involved in 4 patients, including 7 with kidney and 4 with heart involvement, 2 of whom had New York Heart Association class 3 heart failure. All the patients received bortezomib, cyclophosphamide or lenalidomide/thalidomide, and dexamethasone. With a median follow-up of 13 months, 8 of 9 patients had a hematologic response, including 2 who achieved complete response, with a median time to response of 2.7 months. An organ response was seen in 7 of 9 patients, including all 4 patients with cardiac involvement. There were no deaths, and only 1 patient had progressive disease. The major toxicity observed was fluid overload and syncope, seen only in patients with heart failure, who eventually achieved a partial or complete response.ConclusionsDose-attenuated triplet regimens achieved rapid hematologic responses with manageable and reversible toxicity in patients with newly diagnosed AL amyloidosis.     

Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10⁻⁴−10⁻⁵ sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.Subject terms: Risk factors, Translational research     

WT1 Gene Expression in Peripheral Blood Before and After Allogeneic Stem Cell Transplantation is a Clinically Relevant Prognostic Marker in AML – A Single-center 14-year Experience

BackgroundThis work summarizes our experience with WT1 monitoring before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Patients and MethodsThe expression of WT1 gene was measured by real-time polymerase chain reaction in peripheral blood according to the European Leukemia Net recommendations. Between May 2005 and August 2019, we analyzed 147 consecutive patients with acute myeloid leukemia with high WT1 expression at diagnosis, transplanted in first (CR1) or second (CR2) complete remission.ResultsAt the time of allo-HSCT, 107 patients had WT1-normal expression (WT1 ≤ 50 copies), and 40 patients had WT1-high expression. The median follow-up was 21 months. The estimated 5-year overall survival and event-free survival was significantly better in the WT1-normal cohort (65% and 57% vs. 37% and 25%; P = .0003 and P < .0001, respectively) and 5-year cumulative incidence of relapse was significantly lower in the WT1-normal group (19% vs. 53%; P < .0001). Five-year non-relapse mortality was not significantly different (20% and 23%). Multivariate analysis revealed WT1-high expression and acute graft-versus-host disease grade 3/4 as significantly negative prognostic factors for OS. Overall, 49 patients developed WT1 molecular relapse in the post-transplant period; in 14 cases, the therapeutic intervention was done. In all but 1 relapsed patient where WT1 minimal residual disease (MRD) was monitored (38 patients), we detected WT1-high levels (sensitivity of 97%).ConclusionThe results of the analysis confirmed our previous experience that WT1 status before allo-HSCT is a strong prognostic factor for both OS and relapse risk. In addition, we confirmed the usefulness of this marker for MRD monitoring after allo-HSCT. The main advantage is the possibility of frequent MRD monitoring in peripheral blood and early bone marrow examination based on WT1-high expression.     

Efficacy of Haploidentical Hematopoietic Stem Cell Transplantation Compared With Chemotherapy as Postremission Treatment of Children With Intermediate-risk Acute Myeloid Leukemia in First Complete Remission

BackgroundThe role of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for children with intermediate-risk acute myeloid leukemia (IR-AML) in first complete remission has been controversial. The present study compared the effect of chemotherapy with unmanipulated haplo-HSCT as treatment of patients with IR-AML in first complete remission (CR1).Patients and MethodsWe retrospectively analyzed the outcomes of 80 children with IR-AML and compared the effects of chemotherapy (n = 47) with those of haplo-HSCT (n = 33) as treatment in CR1.ResultsThe 3-year overall survival, event-free survival (EFS), and cumulative incidence of relapse (CIR) was 85.4% ± 4.1%, 73.2% ± 5.0%, and 25.4% ± 4.5%, respectively. Compared with the chemotherapy group, the patients in the haplo-HSCT group had a lower CIR (P = .059) and better EFS (P = .108), but roughly equivalent overall survival (P = .841). Multivariate analysis revealed chemotherapy and minimal residual disease (MRD) of ≥ 10^?3 after induction therapy as independent risk factors affecting CIR and EFS. EFS (P = .045) and CIR (P = .045) differed significantly between the 2 treatment groups in patients with MRD of ≥ 10^?3 after induction therapy.ConclusionHaplo-HSCT might be a feasible option for children with IR-AML in CR1, especially for patients with MRD of ≥ 10^?3 after induction therapy.     

Significant efficacy of 2-chlorodeoxyadenosine± rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up

BackgroundSplenic marginal zone lymphoma with or without villous lymphocytes (SLVL/SMZL) is an indolent lymphoma that typically affects elderly patients and that has a median survival >10 years. It presents with marked splenomegaly. Treatment is required in symptomatic cases. Splenectomy remains one of the first-line options in patients fit for surgery. The best pharmacological strategy has not yet been identified for poor surgical risk cases. Among different possible chemotherapeutic approaches, purine analogs, alone or in association with Rituximab, seem to be a valid therapeutic choice.Patients and methodsFifty SMZL patients were treated with Cladribine ± anti-CD20 monoclonal antibody.ResultsForty-seven of 50 patients were evaluable for response. ORR was 87%: 24 of 47 patients (51%) achieved a complete hematological response (CR), 17 of 47 (36%) a partial response (PR) and 6 (13%) resulted unresponsive. Interestingly, 15 of 24 cases (62%) in CR achieved also a molecular remission. After a median follow-up of 48 months, 7 of 41 responsive cases relapsed and the 5-year PFS was 80%.ConclusionsThese data confirm the efficacy of this schedule emphasizing the impact of minimal residual disease even in the outcome of SMZL patients.