scholarly journals Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up

2020 ◽  
Vol 4 (16) ◽  
pp. 3952-3959
Author(s):  
Jorge J. Castillo ◽  
Kirsten Meid ◽  
Catherine A. Flynn ◽  
Jiaji Chen ◽  
Maria G. Demos ◽  
...  
Keyword(s):  
Median Time ◽  
Progression Free Survival ◽  
Primary Treatment ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Mutational Status ◽  
Long Term Follow Up ◽  
Treatment Naïve

Abstract Proteasome inhibition is a standard of care for the primary treatment of patients with Waldenström macroglobulinemia (WM). We present the long-term follow-up of a prospective, phase II clinical trial that evaluated the combination of ixazomib, dexamethasone, and rituximab (IDR) in 26 treatment-naive patients with WM. IDR was administered as 6 monthly induction cycles followed by 6 every-2-month maintenance cycles. The MYD88 L265P mutation was detected in all patients, and CXCR4 mutations were detected in 15 patients (58%). The median time to response (TTR) and time to major response (TTMR) were 2 and 6 months, respectively. Patients with and without CXCR4 mutations had median TTR of 3 months and 1 month, respectively (P = .003), and median TTMR of 10 months and 3 months, respectively (P = .31). The overall, major, and very good partial response (VGPR) rates were 96%, 77%, and 19%, respectively. The rate of VGPR in patients with and without CXCR4 mutations were 7% and 36%, respectively (P = .06). The median progression-free survival (PFS) was 40 months, the median duration of response (DOR) was 38 months, and the median time to next treatment (TTNT) was 40 months. PFS, DOR, and TTNT were not affected by CXCR4 mutational status. The safety profile was excellent with no grade 4 adverse events or deaths to date. IDR provides a safe and effective frontline treatment option for symptomatic patients with WM. This study was registered at www.clinicaltrials.gov as #NCT02400437.

scholarly journals Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial

2020 ◽  
Vol 4 (23) ◽  
pp. 6009-6018
Author(s):  
Meletios Dimopoulos ◽  
Ramon Garcia Sanz ◽  
Hui-Peng Lee ◽  
Marek Trneny ◽  
Marzia Varettoni ◽  
...  
Keyword(s):  
Partial Response ◽  
Progression Free Survival ◽  
Waldenström Macroglobulinemia ◽  
Activating Mutations ◽  
Waldenstrom Macroglobulinemia ◽  
Mutational Status ◽  
Major Response ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Poor Outcomes

Abstract Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

scholarly journals Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia: Long-Term Follow-Up of CALGB Study 9712

2011 ◽  
Vol 29 (10) ◽  
pp. 1349-1355 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Amy S. Ruppert ◽  
Nyla A. Heerema ◽  
Bercedis L. Peterson ◽  
John G. Gribben ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Variable Region ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Mutational Status ◽  
Long Term Follow Up

Purpose The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited. Methods We report the long-term follow-up of the chemoimmunotherapy trial CALGB 9712 from the Cancer and Leukemia Group B, for which treatment regimen was previously reported, to examine end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN). Results A total of 104 patients were enrolled on this study and now have a median follow-up of 117 months (range, 66 to 131 months). The median OS was 85 months, and 71% of patients were alive at 5 years. The median PFS was 42 months, and 27% were progression free at 5 years. An estimated 13% remained free of progression at almost 10 years of follow-up. Multivariable models of PFS and OS showed that immunoglobulin heavy chain variable region mutational status was significant for both, whereas cytogenetic abnormalities were significant only for OS. No patient developed t-MN before relapse. Conclusion Long-term follow-up of CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab. Patients treated with fludarabine plus rituximab administered concurrently or sequentially have a low risk of t-MN. These long-term data support fludarabine plus rituximab as one acceptable first-line treatment for symptomatic patients with CLL.

scholarly journals Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia

Leukemia ◽  
2021 ◽  
Author(s):  
Jorge J. Castillo ◽  
Kirsten Meid ◽  
Joshua N. Gustine ◽  
Carly Leventoff ◽  
Timothy White ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Final Report ◽  
Minor Response ◽  
Upper Respiratory Infection ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Major Response ◽  
Treatment Naïve ◽  
A Minor

AbstractHerein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

scholarly journals Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia

2020 ◽  
pp. JCO.20.00555
Author(s):  
Steven P. Treon ◽  
Kirsten Meid ◽  
Joshua Gustine ◽  
Guang Yang ◽  
Lian Xu ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Response Rates ◽  
Immunoglobulin M ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Major Response ◽  
Previously Treated Patients ◽  
Previously Treated

PURPOSE We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM). PATIENTS AND METHODS Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity. RESULTS The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL ( P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88Mut CXCR4Mut. Conversely, four patients who had MYD88WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88Mut CXCR4WT and MYD88Mut CXCR4Mut WM, respectively ( P = .02). In patients with MYD88WT, the median PFS was 0.4 years ( P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management. CONCLUSION Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.

scholarly journals Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 276-281 ◽  
Author(s):  
Steven P. Treon ◽  
Jacob D. Soumerai ◽  
Zachary R. Hunter ◽  
Christopher J. Patterson ◽  
Leukothea Ioakimidis ◽  
...  
Keyword(s):  
Late Onset ◽  
Treatment Options ◽  
Complete Response ◽  
Infectious Complications ◽  
Lymphoplasmacytic Lymphoma ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Long Term Follow Up

Abstract CD52 is expressed on malignant cells in lymphoplasmacytic lymphoma (LPL), including IgM-secreting Waldenström macroglobulinemia (WM). We examined the activity of alemtuzumab in 28 symptomatic LPL (27 IgM and 1 IgA) patients. The median prior number of therapies for these patients was 2 (range, 0-5) and 43% had refractory disease. Patients received alemtuzumab at 30 mg IV 3 times weekly for up to 12 weeks after test dosing, and also received hydrocortisone, acyclovir, and Bactrim or equivalent prophylaxis. Patients had a complete response (n = 1), a partial response (n = 9), or a MR (n = 11) for an overall and major response rate of 75% and 36%, respectively. Median serum Ig decreased from 3510 to 1460 mg/dL (P < .001 at best response). With a median follow-up of 64 months, the median time to progression was 14.5 months. Hematologic and infectious complications, including CMV reactivation, were more common in previously treated patients and were indirectly associated with 3 deaths. Long-term follow-up revealed late-onset autoimmune thrombocytopenia (AITP) in 4 patients at a median of 13.6 months after therapy, which contributed to 1 death. Alemtuzumab is an active therapy in patients with LPL, but short- and long-term toxicities need to be carefully weighed against other available treatment options. Late AITP is a newly recognized complication of alemtuzumab in this patient population. This study is registered at www.clinicaltrials.gov as NCT00142181.

Abstract TP127: Mortality and Recurrence in Atherosclerotic Ischemic Stroke: Long-term Follow-up

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Miguel A Barboza ◽  
Rodrigo Uribe ◽  
Fabiola Serrano ◽  
Luis C Becerra-Pedraza ◽  
D. K Mantilla-Barbosa ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Outcome ◽  
Median Time ◽  
Smoking History ◽  
Stroke Recurrence ◽  
Active Smoking ◽  
Long Term Outcome ◽  
Long Term Follow Up

Background and purpose: Atherosclerotic ischemic stroke is the second most frequent etiology of stroke in the adult population. Functional outcome, mortality and recurrence of stroke rates on the long-term follow-up are poorly studied. This study investigates long-term outcome among patients with ischemic stroke secondary to atherosclerotic causality, and identifies the main factors associated with poor outcome, recurrence, and death. Methods: We analyzed data from our consecutive acute ischemic stroke database, over a period of 25 years (1990-2015). The endpoints were: bad outcome (Modified Rankin Score ≥3), recurrence and mortality at discharge, and final follow-up. Multivariate Cox and Kaplan-Meier analysis were used to estimate the probability of death and recurrence. Results: A total of 946 consecutive atherosclerotic stroke patients were included (571 [60.4%] males, median age 65 years [interquartile range 57-73 years] for the entire population); dyslipidemia (64.2%), hypertension (63.3%), diabetes (35.0%), and active smoking history (31.8%) were the most prevalent risk factors.After a median follow-up of 38 months (IQR 12-75 months), 59.3% patients had a bad outcome at discharge. A result of 26.1% had stroke recurrence (median time until recurrence: 9 months [IQR 12-84 months], with 12.9% cases presenting ≥2 recurrences), and 24.1% were dead (median time to death: 18.5 months [IQR 11-74 months]) at the final follow-up period. After multivariate adjustment, hypertension (HR 4.2, CI 95% 2.8-6.1; p<0.001) was the strongest predictor of recurrence. Additionally, diabetes (HR 2.6, CI 95% 2.0-3.5; p<0.001), bad functional outcome after recurrence (HR 2.3, CI 95% 1.9-2.9; p<0.001), age ≥65 years (HR 2.2, CI 95% 1.7-2.9; p<0.001), and active smoking (HR 1.8, CI 95% 1.3-2.3; p<0.001) were the strongest predictors of mortality. Conclusions: Atherosclerotic ischemic stroke has a high rate of recurrence, associated mainly with hypertension. Mortality is predicted by diabetes, bad functional outcome at recurrence, and older age.

scholarly journals Nontransplant therapy for bone marrow failure

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Danielle M. Townsley ◽  
Thomas Winkler
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Single Agent ◽  
Telomere Attrition ◽  
Long Term Follow Up ◽  
Treatment Naïve

Abstract Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be required less frequently. That trilineage hematologic responses could be achieved with the single agent eltrombopag in refractory aplastic anemia promotes new interest in growth factors after years of failed trials using other growth factor agents. Preliminary results adding eltrombopag to immunosuppressive therapy are promising, but long-term follow-up data evaluating clonal evolution rates are required before promoting its standard use in treatment-naive disease. Danazol, which is traditionally less preferred for treating cytopenias, is capable of preventing telomere attrition associated with hematologic responses in constitutional bone marrow failure resulting from telomere disease.

T1 Top Line Results of the DETECT Enzymatic Debridement Multicenter Randomized Controlled Trial

2020 ◽  
Vol 41 (Supplement_1) ◽  
pp. S1-S1
Author(s):  
William L Hickerson ◽  
Jeremy Goverman ◽  
Sigrid A Blome-Eberwein ◽  
Adam Singer ◽  
Lucy Wibbenmeyer
Keyword(s):  
Median Time ◽  
Wound Closure ◽  
The United States ◽  
Acute Stage ◽  
Phase Iii ◽  
Randomized Controlled ◽  
Multicenter Randomized Controlled Trial ◽  
Long Term Follow Up

Abstract Introduction Bromelain Based Debridement (BBD) of deep burns is approved for use in Europe, Argentina, Russia, South Korea, Peru and Israel. In the United States it is an investigational product and currently there are 2 multicenter RCTs (DETECT – adults, CIDS – children). Patient enrollment in the DETECT adult trial has been completed. The aim of this abstract is to present the acute stage top line results of the DETECT trial. Methods 175 adult patients suffering from deep burns were included in a phase III multicenter, multinational, randomized, controlled, assessor blinded trial. Patients were randomized to 3 arms – BBD, Standard of Care (SOC), or Gel vehicle (Placebo control) in a 3:3:1 ratio (75 BBD, 75 SOC, 25 Gel). The primary endpoint was the incidence of complete eschar removal (BBD vs Gel). Additional acute stage endpoints included the time to complete eschar removal, incidence of surgical eschar removal and eschar removal associated blood loss.Time to complete wound closure (BBD vs SOC) was assessed as a safety endpoint. Following the acute stage, a long-term follow up period of 2 years is being conducted. Results Patient demographics and wound baseline characteristics were comparable across study arms.The incidence of complete eschar removal was significantly higher for BBD vs Gel patients (93.3% vs 4%, p&lt; 0.0001). The incidence of surgical eschar removal was significantly lower for BBD vs SOC patients (4% vs 72%, p&lt; 0.0001). The median time to complete eschar removal was significantly shorter for BBD vs SOC patients (1 day vs 3.8 days, p&lt; 0.0001). Calculated eschar removal associated blood loss was significantly lower for BBD vs SOC patients (14ml vs 815ml, p&lt; 0.0001). The median time to complete wound closure was similar for BBD and SOC patients (27 and 28 days). The overall safety profile of BBD treated patients was good and consistent with the safety data known from previous studies.The results of the long term follow up period are not yet available. Conclusions The acute stage results of this robust phase III RCT demonstrate the safety and efficacy of BBD and are in line with previous trial results. Applicability of Research to Practice The results of this trial may help pave the way for US approval of BBD.

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