Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib.
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ABSTRACT:
SUBMITTER: Ravichandran S
PROVIDER: S-EPMC8217489 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTreatment protocols for light chain (AL) amyloidosis have been derived from myeloma treatment. Bortezomib is a key drug used for the treatment of myeloma and AL amyloidosis. We retrospectively investigated the efficacy and toxicity of bortezomib- based chemotherapy in patients with newly diagnosed AL amyloidosis.MethodsWe reviewed the outcomes of newly diagnosed autologous stem cell transplantation (auto-SCT)-ineligible AL amyloidosis patients who received bortezomib-based chemotherapy at a referral center between 2011 and 2017.ResultsOf 63 patients who received bortezomib-based chemotherapy, 32 were male, and the median age was 66 years (range, 42‒82 yr). The hematologic overall response rate (ORR) was 65.1%, and the chemotherapy regimen with the best hematologic response was VMP (75.7%, 28/37). Sixty patients had significant organ (heart or kidney) involvement; 28.3% of patients (N=17) had major organ responses after chemotherapy. With a median follow- up of 34 months, there was no significant difference in progression-free survival (P=0.49) or overall survival (P =0.67) according to regimen. Most hematologic and non-hematologic problems were manageable.ConclusionVarious chemotherapy combinations based on bortezomib are currently employed in the clinical setting, but no difference was found in terms of efficacy or toxicity.
| S-EPMC8721454 | biostudies-literature
Project description:Autologous stem cell transplant (ASCT) is highly effective in selected patients with light chain (AL) amyloidosis. Bortezomib, preceding or following ASCT, improves responses. Satisfactory responses, including at least a partial response, very good partial response (VGPR) with organ response, or complete response, can be observed after induction therapy alone. We report 139 patients treated upfront with cyclophosphamide/bortezomib/dexamethasone (CyBorD), followed by ASCT only if response was unsatisfactory. Only 1 treatment-related death was observed. After CyBorD, hematologic response (HR) rate was 68% (VGPR or better, 51%), with 45% satisfactory responses. Transplant was performed in 55 (40%) subjects and resulted in an 80% HR rate (65% ≥ VGPR). Five-year survival was 86% and 84% in patients treated with ASCT or CyBorD alone, respectively (P = .438). Also, 6- and 12- month landmark analyses did not show differences in survival. Duration of response was not different in the 2 groups (60 vs 49 months; P = .670). Twenty-one (15%) patients with an unsatisfactory response to CyBorD could not undergo ASCT because of ineligibility or refusal; instead, they received rescue chemotherapy, with HR in 38% of cases and 51% 5-year survival. This sequential response-driven approach, offering ASCT to patients who do not attain satisfactory response to upfront CyBorD, is very safe and effective in AL amyloidosis.
| S-EPMC7479942 | biostudies-literature
Project description:Bortezomib, in combination with dexamethasone (VD) or with the addition of cyclophosphamide (VCD), is highly effective in patients with amyloid light-chain (AL) amyloidosis. Currently, VCD is considered as a primary regimen for patients with AL, but it is not clear whether the addition of cyclophosphamide to VD further and significantly improves efficacy, given the substantial activity of bortezomib itself. We retrospectively compared the outcomes of 101 patients with AL amyloidosis who received VD (n=59) or VCD (n=42) in two consecutive periods. Early mortality after adjustment for Mayo stage was similar. On intent to treat, a hematologic response rate was 68% for patients treated with VD and 78% for VCD (P=0.26), while complete response+very good partial response (CR+VGPR) rate was 47.5% and 35%, respectively. Higher doses of dexamethasone or twice-weekly bortezomib were not associated with significantly higher CR+VGPR rates. Organ responses occurred in similar rates between the two groups. Median survival was similar (33 vs 36 months, P=0.45) even after adjustment for Mayo stage and dose and schedule of bortezomib and dexamethasone. In conclusion, bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of cyclophosphamide do not seem to have a profound effect on efficacy and survival.
| S-EPMC5520394 | biostudies-literature
Project description:Autologous stem cell transplantation (ASCT) has been used as treatment for immunoglobulin light-chain (AL) amyloidosis for over two decades with improving outcomes; however, the majority of patients are not candidates for this therapy at diagnosis. Novel agents such as immunomodulatory drugs, proteasome inhibitors, and immunotherapy with monoclonal antibodies targeting CD38 have been adopted from the multiple myeloma spheres with encouraging results. Herein, we discuss the role of daratumumab, a monoclonal antibody to CD38, in the treatment of AL amyloidosis. We focus on its mechanism of action, tolerability, and the current published data on its use in AL amyloidosis. Early data from phase I and phase II studies show that daratumumab is tolerated well in this population and induces rapid and deep responses. Phase III trials are currently accruing and we envision daratumumab becoming a key component in the treatment of AL amyloidosis in the future.
| S-EPMC6342668 | biostudies-literature
Project description:Lenalidomide is an immunomodulatory agent used to treat plasma cell dyscrasias. We previously observed worsening of kidney function in a high proportion of patients with AL amyloidosis during lenalidomide treatment. The objective of this study is to characterize alterations in kidney function among patients with AL amyloidosis undergoing treatment with lenalidomide.This is a secondary analysis of an ongoing clinical trial at a single referral centre. Forty-one patients with AL amyloidosis received lenalidomide with or without dexamethasone in monthly cycles. Kidney dysfunction was defined as ? 50% increase in serum creatinine. Severe kidney dysfunction was defined as ? 100% increase in serum creatinine. Recovery of renal function was defined as a return of serum creatinine to within 25% of the pre-treatment value or discontinuation of dialysis.Twenty-seven of 41 patients (66%) developed kidney dysfunction during lenalidomide treatment. The kidney dysfunction was severe in 13 of these patients (32%); four of whom required initiation of dialysis (10%). The median time to kidney dysfunction after starting lenalidomide was 44 days (interquartile range 15-108 days). Four of eight patients without underlying renal amyloidosis developed kidney dysfunction. Patients with severe kidney dysfunction were older and had a higher frequency of underlying renal amyloidosis, greater urinary protein excretion, and lower serum albumin. Recovery of renal function occurred in 12 patients (44%).Among patients with AL amyloidosis, worsening of kidney function occurs frequently during lenalidomide treatment. While a causal role of the drug has not been established, our findings suggest that kidney function should be monitored closely during treatment with this drug.
| S-EPMC3108346 | biostudies-other
Project description:BackgroundThe natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach.MethodsWe retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes.ResultsResponse rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p < 0.05), a higher complete cytogenetic response rate (45% vs 10.7%, p < 0.001), and more patients proceeding to ASCT (32.5% vs 10.7%, p < 0.01). With a median follow-up of 6.7 years, long-term outcomes were similar between the IC + TKI and HMA + TKI groups. Combination therapy with IC/HMA + TKI was superior to therapy with TKI alone, including when analysis was limited to those treated with a 2nd/3rd-generation TKI. When using a 2nd/3rd-generation TKI, IC/HMA + TKI led to lower 5-year cumulative incidence of relapse (CIR; 44% vs 86%, p < 0.05) and superior 5-year event-free survival (EFS; 28% vs 0%, p < 0.05) and overall survival (OS; 34% vs 8%, p = 0.23) compared to TKI alone. Among patients who received IC/HMA + TKI, EFS and OS was superior for patients who received a 2nd/3rd generation TKI compared to those who received imatinib-based therapy. In a landmark analysis, 5-year OS was higher for patients who proceeded to ASCT (58% vs 22%, p = 0.12).ConclusionsCompared to patients treated with TKI alone for CML-MBP, treatment with IC + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. Combination therapy with IC + TKI or HMA + TKI, rather than a TKI alone, should be considered the optimal treatment strategy for patients with CML-MBP.
| S-EPMC8204504 | biostudies-literature
Project description:Systemic light-chain (AL) amyloidosis is caused by a small B cell, most commonly a plasma cell (PC), clone that produces toxic light chains (LC) that cause organ dysfunction and deposits in tissues. Due to the production of amyloidogenic, misfolded LC, AL PCs display peculiar biologic features. The small, indolent plasma cell clone is an ideal target for anti-CD38 immunotherapy. A recent phase III randomized study showed that in newly diagnosed patients, the addition of daratumumab to the standard of care increased the rate and depth of the hematologic response and granted more frequent organ responses. In the relapsed/refractory setting, daratumumab alone or as part of combination regimens gave very promising results. It is likely that daratumumab-based regimens will become new standards of care in AL amyloidosis. Another anti-CD38 monoclonal antibody, isatuximab, is at an earlier stage of development as a treatment for AL amyloidosis. The ability to target CD38 on the amyloid PC offers new powerful tools to treat AL amyloidosis. Future studies should define the preferable agents to combine with daratumumab upfront and in the rescue setting and assess the role of maintenance. In this review, we summarize the rationale for using anti-CD38 antibodies in the treatment of AL amyloidosis.
| S-EPMC7998921 | biostudies-literature
Project description:Despite successful treatment of the clonal plasma cell implicated in its pathogenesis, patients with AL amyloidosis (AL) experience significant morbidity related to underlying amyloid mediated organ dysfunction. While normalization of the serum free light chain measurements [normal ratio of involved and uninvolved free light chains (nFLCr)] is the goal of therapy and centerpiece of hematologic response criteria, achieving (or not achieving) meaningful organ response (OR) is clinically significant for its implications on long-term symptomatology as well as overall survival (OS), and remains the ultimate goal of treatment. Expectations for organ recovery following successful therapy leading to nFLCr in AL remain poorly described. We evaluated the timeframe and predictive factors for OR, and long-term outcome, in 313 AL patients who achieved nFLCr following therapy initiation. OR was seen in 80% of surviving AL patients within 1-year of nFLCr. Patients achieving early OR within 1 year of nFLCr had superior OS compared with those who despite obtaining nFLCr did not achieve early OR. We further evaluated factors predicting OR and OS among patients achieving nFLCr. Higher values of dFLC (involved-uninvolved) at diagnosis predict OR, and early OR predicts improved OS following successful hematologic therapy in AL.
| S-EPMC5780648 | biostudies-literature
Project description:Newly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo: n = 473; validation cohort, Pavia: n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using incremental scoring based on hazard ratios with scores of 0-3 for HR (0-CR, 1-VGPR, 2-PR, 3-no response) and 0-2 for OR (0-AOR, 1-MOR, 2-NOR). Patients could be divided into two distinct CHOR groups (scores 0-3 and 4-5), with median OS in group 1 and group 2: Not reached vs. 34 months, p < 0.001 [Mayo] and 87 vs. 23 months, p < 0.001 [Pavia]. In conclusion, we developed a model that can assess multiple organs concurrently, and integrate both HR and OR assessments to determine early clinical benefit with treatment, which may be used as a surrogate end-point in trials and to compare outcomes with different therapies.
| S-EPMC7156647 | biostudies-literature
Project description:Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) "light" regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10-5), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.
| S-EPMC6849948 | biostudies-literature