Lenalidomide and Dexamethasone in the Treatment of AL Amyloidosis: Final Results of A Phase II Trial

Abstract Abstract 4084 AL amyloidosis is a plasma cell dyscrasia in which clonal immunoglobulin light chains misfold, forming fibrils that are deposited in tissues and vital organs. Immunomodulatory drugs including thalidomide, lenalidomide (LEN), and pomalidomide have activity in AL amyloidosis. We conducted a prospective phase II trial of LEN with dexamethasone (DEX) in the treatment of AL amyloidosis (ClinicalTrials.gov: NCT00091260), enrolling 82 patients from 2004–2011. We now report the final results of this trial. The majority of the patients were treated with LEN at a starting dose of 15 mg/d for 21 days out of a 28 day cycle, and received DEX at 20 or 40 mg weekly, depending upon age, congestive heart failure, and/or peripheral edema, and aspirin prophylaxis for venous thromboembolism (VTE) was used for most. Of the 82 patients, the median age was 62 (range, 40–84) and 63% were men. 95% of the patients had prior therapy for AL, often including high dose melphalan and autologous stem cell transplantation. The median number of cycles delivered was 11 (range, 1–69). Of the 68 evaluable patients, 16% achieved a complete hematologic response, 44% achieved a partial hematologic response, 9% achieved a minor hematologic response, and 29% had no response to treatment. The median time to best hematologic response was 6 months. Sixty-three patients had quantifiable organ involvement prior to treatment with LEN/DEX, and 44% of those patients had measurable organ response. Reasons for discontinuation of study drug were side effects (29%), non-response (39%) and complete response or completion of trial (15%). The most common side effects during treatment were fatigue (88%), anemia (67%), muscle cramps (66%), dizziness/lightheadedness (60%), respiratory tract infections (55%), increased creatinine (56%) and skin rash (48%). In conclusion, LEN administration achieved a 60% hematologic response rate (CR+PR) even in heavily pre-treated AL patients, when used at a starting dose of 15 mg/d with weekly dose-modified DEX, VTE prophylaxis, and appropriate management of side effects. Disclosures: Off Label Use: Lenalidomide for AL amyloidosis. Sanchorawala:Millennium: Research Funding. Zeldis:Celgene: Employment. Seldin:Celgene: Research Funding.

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Phase II Trial of Pulse Dosed Lenalidomide In Previously Treated Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v116.21.1383.1383 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1383-1383 ◽

Cited By ~ 1

Author(s):

Georg Aue ◽

Susan Soto ◽

Janet Valdez ◽

Diane C Arthur ◽

Xin Tian ◽

...

Keyword(s):

Side Effects ◽

Chronic Lymphocytic Leukemia ◽

Partial Response ◽

Phase Ii ◽

Stable Disease ◽

Phase Ii Trial ◽

Lymphocytic Leukemia ◽

Bulky Disease ◽

Starting Dose ◽

Duration Of Response

Abstract Abstract 1383 Introduction: Lenalidomide (L) has activity in relapsed chronic lymphocytic leukemia (CLL). The mechanism of action is not well understood but may involve stimulation of anti-leukemic immune responses. Myelosuppression especially neutropenia is a concerning side effect. We reasoned that pulsed dosing of lenalidomide could reduce myelosuppression while maintaining the immune stimulatory effect. To test this concept we initiated a single center, phase II trial (ClinicalTrials.gov Identifier: NCT00465127) of lenalidomide given in cycles of 3 weeks on, 3 weeks off drug (42 day cycles). Methods: Patients (pts) with relapsed CLL or small lymphocytic lymphoma with ANC>500/ul and platelets >20,000/ul were eligible. The primary endpoint defined as response after 4 cycles has been recorded for all participants. Pts with partial response were allowed to receive up to 4 additional cycles. The starting dose for the first 10 pts was 20 mg daily; the starting dose for pt 11 onwards was lowered to 10 mg daily because of toxicities observed in other L trials for CLL. TLS prophylaxis with Allopurinol was mandated during cycle 1–3. Deep venous thrombosis (DVT) prophylaxis was not mandated unless risk factors were present. Ibuprofen and corticosteroids were allowed to treat symptoms of a cytokine release syndrome (CRS, defined by LN swelling, fever, fatigue, pain, chills, dehydration). Responses were assessed by IWCLL criteria and included CT scanning. Patient characteristics (n=33) were: median age 64 years (36-78); median number of prior therapies 3 (range 1–7); 52% Rai stage III-IV; 70% bulky disease; 30% fludarabine refractory; 56% (of 27 pts) ZAP70 pos; 64% (of 25 pts) unmutated immune globulin VH mutation status; 43% del 17p; 15% del 11q. Results: A total of 131 cycles of L were given. 31 pts received at least 2 cycles of therapy (range 2–8) and were evaluable for response: 5 (16%) partial response (PR), 18 (58%) stable disease, and 8 (26%) progressive disease. 4 of 5 responding pts had del 17p and bulky disease. In responders (n=5, PR) vs non responders (n=26, SD+PD) the PFS was 16 vs 6 months (p>0.01), and the time to next therapy was 17 vs 6 months (p>0.01), respectively. Once treatment was stopped, duration of response was short lived (median 6 months, range 2–18). 4 out of 5 responders were observed in the 20 mg dose starting group versus only 1 responder in the 10 mg group (p=0.03). There was no difference in the CRS score between the 2 groups (2.5 vs 1.5, p=0.17). Hematologic responses were observed in 11 out of 24 CLL pts (45%). At the completion of 4 cycles CD4 and CD8 counts increased by 20%, while NK cell counts remained unchanged. Dose modifications/withdrawl: 41% of cycles required dose adjustments prior to or during cycles 1–4. 9 pts (27%) did not complete 4 cycles of L because of: autoimmune cytopenias (2 pts), side effects (4 pts; CRS 1 pt, neutropenia 3 pts), withdrawal from study (2 pts), and disease progression (1 pt). Toxicity: Gr 3/4 neutropenia was observed in 56% of 131 cycles, often worsening with cumulative cycles. Gr 3/4 thombocytopenia and anemia were seen in 30% and 15% of cycles, respectively. Gr 1/2 and 3/4 infections occurred in 23% and 11% of cycles, respectively, 8 of those in the setting of neutropenia. Gr 3 CMV colitis, PCP pneumonia and Candedemia each were observed once. 1 patient died from streptococcal sepsis in cycle 4. Gr 1/2 and 3/4 CRS were observed in 43% and 10% of cycles, respectively. A CRS was encountered in 78% of first cycles typically within the first week, and in 48%, 38% and 30% of cycles 2–4, respectively. 6 DVTs (Gr 3) were diagnosed in 5 pts. Other common side effects were fatigue (62%), rash (39%) and muscle cramps (27%), all Gr 1/2. No case of tumor lysis syndrome was seen. Conclusion: L cycled 3 weeks on, 3 weeks off led to stable disease in the majority of pts and induced PRs in 16% of relapsed CLL patients with high risk disease. Pulse dosing of L did not lead to reduced toxicities. Myelosuppression and infections remain a major concern. 4 out of 5 responders were observed in the 20 mg cohort arguing for higher L starting doses. Notably, side effects, particularly the CRS, were similar in the two cohorts. Once L was discontinued, the duration of response was short, suggesting a need for continued therapy in pts who are able to tolerate the drug. Disclosures: Off Label Use: Lenalidomide is not FDA approved in Chronic Lymphocytic leukemia.

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A Phase II Trial of Myeloablative I-131-Tositumomab, Etoposide and Cyclophosphamide Followed by Autologous Transplantation for B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v120.21.811.811 ◽

2012 ◽

Vol 120 (21) ◽

pp. 811-811

Author(s):

Ajay K. Gopal ◽

Ted A. Gooley ◽

Joseph Rajendran ◽

John M. Pagel ◽

Darrell R. Fisher ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Autologous Transplantation ◽

Prospective Trial ◽

Absorbed Dose ◽

Whole Body ◽

High Dose ◽

Hematopoietic Stem

Abstract Abstract 811 Background: High-dose therapy and autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for many patients (pts) with high-risk or relapsed B-cell non-Hodgkin lymphoma (B-NHL). Despite the use of transplant, relapse is likely for most with indolent or mantle cell lymphoma (MCL) as well as for aggressive B-NHL recurring after rituximab (R)-based chemotherapy. Total body irradiation (TBI) has been incorporated into ASCT regimens to overcome chemotherapy resistance and improve outcomes, but studies to date indicate that escalation of TBI is not feasible due to toxicity in non-target organs. We hypothesized that radioimmunotherapy (RIT) could supplant TBI and identified the maximally tolerated dose (MTD) of high-dose RIT using I-131-tositumomab that could be safely combined with high-dose etoposide (VP-16) and cyclophosphamide (CY) prior to ASCT (Press, Blood 2000). We now present the mature data of a large prospective phase II trial at the MTD of high-dose I-131-tositumomab, VP-16, and CY. Methods: Pts were eligible if they were <60 years of age, had MCL in first remission or any relapsed/refractory B-NHL, an ECOG PS of 0–1, acceptable organ function, >2×106 autologous CD34+ peripheral blood stem cells/kg collected, <20 Gy prior radiation to critical organs, and no human-anti-mouse-antibodies. All pts underwent outpatient biodistribution studies using tositumomab (1.7 mg/kg, n= 64 or 485mg flat dose, n= 43) labeled with ∼10mCi I-131 followed by serial quantitative gamma camera imaging to calculate individualized organ-specific absorbed dose estimates. Pts then received therapeutic infusions of I-131-tositumomab to deliver 25Gy to the critical normal organ receiving the highest radiation absorbed dose. When residual radiation was <7mR/hr at 1m (median 10 days) pts received 60mg/kg VP-16 followed 48 hours later by 100mg/kg CY. ASCT occurred when residual radiation was <2mR/hr at 1m. Toxicity was scored on the Bearman transplant scale and CTCAE 2.0. Response followed standard criteria. Results: Between June 1999 and April 2011 107 pts were transplanted on this protocol. Baseline characteristics included: median age 52 yrs (range 32–60), stage III/IV = 104 (97%), median number of prior regimens = 3 (range 1–11), prior R = 98 (92%), R refractory = 35 (33%), chemoresistant disease (defined as < a partial response [PR] to the most recent regimen) = 41 (40%), >1 extranodal site = 36 (33%), elevated LDH = 46 (42%). Histological strata: Indolent 43% (45 follicular lymphoma [FL], 1 lymphoplasmacytic lymphoma), MCL = 31%, Aggressive 27% (27 diffuse large B-cell including 12 with transformed disease, 2 Burkitt's). Dose limiting critical normal organs receiving up to 25Gy included lung (71), liver (29), kidney (6), and heart (1) from a median administered I-131 activity of 557 mCi (range 231–1353) resulting in a median whole body dose of 4.4Gy. ASCT occurred an average of 14 days after the I-131-tositumomab infusion with a median of 5.9×106 CD34/kg (range 2–20×106 CD34/kg). An unsupported ANC>500/μL and platelets >20K/μL occurred at a median of day 12 and day 13, respectively. Bearman toxicity of grade III/IV was observed in 6 pts (5.6%) with 3 (3%) non-relapse deaths (all cardiopulmonary toxicity) by day 100. Pulmonary toxicity of ≥ grade 4 CTCAE occurred in 10 (9%) pts. Responses to therapy included: CR/CRu = 87 (81%), PR = 8 (7%), SD = 11 (10%), and PD = 1 (1%). Currently, 76 (71%) pts are alive with 59 (55%) progression-free. The estimated 5-year overall survival (OS), progression-free survival (PFS) and relapse were 72%, 56%, and 36%, respectively (figure, median follow up of 5.2 years). Five-year OS/PFS estimates for the 3 histological groups included indolent (81%/61%), aggressive (69%/51%), and MCL (57%/52%). MCL pts with relapsed/refractory disease had a 5-year OS/PFS of 55%/42%. Multivariable analysis only identified chemoresistant disease as associated with death (HR 3.07 (1.46–6.44, p=.003) and relapse or death (HR 2.12 (1.17–3.86, p=.01). Secondary AML/MDS occurred in 1 patient to-date. Conclusions: This largest prospective trial of myeloablative RIT demonstrates that I-131-tositumomab delivering 225Gy to critical organs along with high-dose VP-16 and CY prior to ASCT is feasible and effective with toxicities comparable to TBI-based regimens. These data provide the foundation for future approaches incorporating RIT into transplant conditioning regimens for lymphoma. Disclosures: Gopal: GSK: Research Funding; Spectrum: Research Funding. Off Label Use: high-dose use of I-131-tositumomab. Rajendran:GSK: Research Funding. Pagel:GSK: Research Funding. Maloney:GSK: Research Funding. Press:GSK: Research Funding.

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Bendamustine, Ofatumumab and High-Dose Methylprednisolone (BOMP) in Relapsed/Refractory CLL: Results of a Planned Interim Analysis of the French CLL Intergroup ICLL01 Phase II Trial

Blood ◽

10.1182/blood.v124.21.3341.3341 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3341-3341 ◽

Cited By ~ 3

Author(s):

Sophie de Guibert ◽

Marie-Sarah Dilhuydy ◽

Loic Ysebaert ◽

Laurence Sanhès ◽

Sylvain Choquet ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Interim Analysis ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Risk Group ◽

High Dose ◽

Color Flow ◽

High Dose Methylprednisolone

Abstract Introduction: For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988). Patients and Methods: Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis. Results: Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively. According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts. Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts' decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4). Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative (<10-4) in 13 (28.8%) cases. Following evaluation, 5 responding pts (9%) had RIC allogeneic (RIC-Allo) transplantation with a persistent remission. With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases. The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p<0.001), del(17p) (9.5 m, p=0.017) and TP53 mutation (9.5 m, p=0.007) groups. Conclusion: Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. Figure 1 Figure 1. Disclosures de Guibert: Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

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Induction with Bortezomib and Dexamethasone (BD) Followed By Risk Adapted High Dose Melphalan and Autologous Stem Cell Transplantation and BD Consolidation in Patients with AL Amyloidosis: A Phase II Feasibility Study

Blood ◽

10.1182/blood.v126.23.3178.3178 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3178-3178 ◽

Cited By ~ 1

Author(s):

Heather Landau ◽

Nicole Montanez ◽

Alexandra Cowan ◽

Hoover Elizabeth ◽

Carlos Flombaum ◽

...

Keyword(s):

Stem Cell ◽

Phase Ii ◽

Research Funding ◽

Treatment Initiation ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Weekly Schedule ◽

Newly Diagnosed ◽

Critical Determinant

Abstract Background: The depth and durability of hematologic response is a critical determinant of outcome in patients (pts) with light chain (AL) amyloidosis. Complete hematologic remissions (CR) following risk-adapted melphalan and stem cell transplant (RA-SCT) in pts with AL amyloidosis is associated with organ improvement and extended overall survival (OS). We have previously shown that using bortezomib and dexamethasone (BD) as consolidation following RA-SCT is associated with deeper hematologic responses and favorable outcomes. We have conducted a prospective phase II trial using BD as induction followed by RA-SCT and BD consolidation to determine the safety and hematologic and organ response rates of this treatment program for newly diagnosed, transplant-eligible pts with AL amyloidosis. Methods: Untreated pts with AL amyloidosis received 1-3 cycles of BD (B 1.3mg/m2, IV/SC, and D 40mg, IV/PO, days 1, 4, 8, 11). BD was discontinued before 3 cycles in patients who achieved CR. Pts were then assigned melphalan 100, 140 or 200mg/m2 based on age, renal function and cardiac involvement; Starting 3 months following RA-SCT, pts received six cycles of BD (B 1.3mg/m2, IV/SC and D 20mg, IV/PO days 1, 8, 15, 22) every 12 weeks as consolidation. Hematologic responses were assessed using International Society of Amyloidosis criteria (Palladini et al. JCO 2012) and organ responses using updated criteria (Palladini et al. Blood 2014), after induction, 3 months post RA-SCT, and at 12 and 24 months from treatment initiation. Patients with New York Heart Association Class III/IV heart failure, ECOG > 2 or > grade 2 neuropathy were ineligible. Results: Twenty pts, 70% male, with a median age of 60.1 years with renal (55%), cardiac (65%), liver/GI (15%) or nervous system (15%) involvement received BD induction and 18 patients have been transplanted. Two pts with cardiac disease died during BD induction (10% TRM); 85% of pts are alive with a median follow up of 28 mo. By intent to treat, 60% and 70% of patients achieved at least a very good partial response (>VGPR) following BD induction and RA-SCT, respectively. Overall, 95% of patients achieved hematologic responses (>PR) including 35% CR. Cardiac and renal responses were seen in 75% (N=8) and 60% (N=10) of evaluable pts at 1 year following treatment initiation. Most common grade >3 adverse events included GI (40%), Renal (30%), infectious (10%), and cardiovascular (10%); Grade 2 or higher neuropathy was seen in 40% of pts and warranted discontinuation of BD consolidation in 35% of pts. Conclusion: In newly diagnosed AL amyloidosis pts, BD induction followed by RA-SCT was safe and rapidly and effectively induced responses resulting in organ improvement. There was 10% TRM during BD induction and no deaths during transplant supporting the notion that early mortality in newly diagnosed AL pts is independent of treatment received. The high incidence of neuropathy may be related to the administration of BD on a twice weekly schedule and rendered some pts ineligible for post-transplant therapy. Whether transplant-eligible pts will ultimately derive more benefit from proteasome inhibitor induction versus consolidation is worthy of further study. Disclosures Landau: Spectrum Pharmaceuticals: Honoraria; Janssen: Consultancy; Janssen: Consultancy; Prothena: Consultancy, Honoraria; Takeda: Research Funding; Onyx: Honoraria, Research Funding. Landgren:Celgene: Honoraria; International Myeloma Foundation: Research Funding; BMJ Publishing: Consultancy; Onyx: Research Funding; Onyx: Consultancy; BMJ Publishing: Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Medscape: Consultancy; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Hassoun:Novartis: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

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A Phase II Trial Comparison of Once Versus Twice Weekly Bortezomib in CYBORD Chemotherapy for Newly Diagnosed Myeloma: Identical High Response Rates and Less Toxicity.

Blood ◽

10.1182/blood.v114.22.616.616 ◽

2009 ◽

Vol 114 (22) ◽

pp. 616-616 ◽

Cited By ~ 2

Author(s):

Craig B. Reeder ◽

Donna E. Reece ◽

Vishal Kukreti ◽

Joseph R. Mikhael ◽

Christine Chen ◽

...

Keyword(s):

Stem Cell ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Response Rates ◽

High Dose ◽

Newly Diagnosed ◽

High Dose Dexamethasone ◽

Grade 3 ◽

Cell Harvest

Abstract Abstract 616 Background: We have shown the three drug combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) to be highly active therapy in newly diagnosed myeloma while allowing stem cell harvest and transplantation (Reeder et al. Leukemia 2009; 23:1337-1341). However, twice weekly bortezomib and high dose dexamethasone have been shown to cause significant toxicities. In a prospective Phase II we modified CyBorD by using bortezomib once weekly and reducing the dexamethasone to “low dose dex” after the first two cycles in an attempt to reduce toxicity (cohort 2). We report the efficacy and toxicity of this modified regimen and compare the results to standard CyBorD (cohort 1). Patients and methods: 63 untreated symptomatic patients were enrolled on this Phase II trial (33 on cohort 1 and 30 on cohort 2). All are evaluable for response and toxicity. Treatment on cohort 2 consisted of oral cyclophosphamide 300 mg/m2 and IV bortezomib 1.5 mg/m2 days 1, 8, 15 and 22 and dexamethasone 40 mg by mouth days 1-4, 9-12, 17-20 in cycles 1 and 2, then 40 mg po days 1, 8, 15, 22 in cycles 3 and beyond. Cohort 1 used standard dosing of bortezomib and high dose dexamethasone throughout. Each cycle was 28 days. Acyclovir and a quinolone antibiotic prophylaxis were routinely used. Patients were evaluated for response and toxicity every cycle and were offered stem cell harvest and transplant after the 4th cycle but could continue up to 12 cycles maximum. Results: The median age for all 63 patients was 61 (36-74) years and 48% were female. Durie-Salmon stages were 47% II and 50% III and ISS stages I 43%, II 36%, and III 21%. Twenty-four percent of patients were genetic high risk (t(4;14) or deletion 17). Cohorts I and II were matched for age, gender and ECOG PS. ISS stages were higher in cohort 1 than cohort 2 (II/III 67% vs. 44%). The intent to treat (ITT) ORR (≥PR) for all 63 patients (cohorts 1 and 2) is 90% with 60% ≥VGPR. For cohort 2 (modified CyBorD) the ITT overall response (≥PR) was 93% (CR: 5, nCR: 7, VGPR: 6, PR: 10) with 60% ≥VGPR and 40% ≥ nCR. Those completing all 4 cycles of therapy had 92% ORR (24/26) and 65% (17/26) ≥VGPR. A comparison of response rates in cohorts 1 and 2 is shown in table 1. These high and comparable response rates were associated with fewer grade 3+ adverse events (AE's) than in cohort 1 (37% vs. 48%) and no grade 3 peripheral neuropathy (PN). The median follow-up for all 63 patients is 12.4 (2.8-29.2) months and 95% of patients are alive with 87% free from progression. Conclusions: Modified CyBorD with weekly bortezomib and reduced dexamethasone retains the high activity seen in standard CyBorD, but is less toxic and more convenient. Interestingly, this modified regimen allowed higher overall doses of bortezomib (5.2 vs. 6.0 mg/m2 per cycle) yet overall neuropathy rates were similar. This combination of a weekly alkylating agent with bortezomib and dexamethasone is well tolerated and produces high response rates in newly diagnosed patients with multiple myeloma. Disclosures: Reeder: Millennium (MPI): Research Funding; Celgene: Research Funding. Reece:Ortho Biotech: Honoraria, Research Funding. Chen:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria. Hentz:Millennium (MPI): Research Funding. Fonseca:Otsuka: Consultancy; BMS: Consultancy; Amgen: Consultancy; Medtronic: Consultancy; Genzyme: Consultancy. Bergsagel:Merck: Research Funding; Amgen: Consultancy; Genentech: Consultancy; Celgene: Consultancy. Stewart:Proteolix: Honoraria; Millennium (MPI): Research Funding.

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Consolidation with a Short Course of Daratumumab Improves Complete Response Rates in Patients with AL Amyloidosis or Lcdd

Blood ◽

10.1182/blood-2018-99-112764 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3246-3246

Author(s):

Efstathios Kastritis ◽

Maria Gavriatopoulou ◽

Fotiou Despina ◽

Ioanna Dialoupi ◽

Dimitrios C. Ziogas ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Steering Committee ◽

High Dose ◽

Al Amyloidosis ◽

Primary Therapy ◽

Advisory Committees ◽

Hematologic Response ◽

Short Course ◽

Travel Grant

Abstract A deep hematologic response (i.e at least a very good partial hematologic response - hemVGPR or a complete hematologic response- hemCR) is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib-based therapy is the mainstay of anti-clonal therapy for patients with AL amyloidosis and 70-80% of patients with previously untreated AL may achieve a hematologic response, however, hemVGPR or better is expected in less than 50%. Given that clones in AL are often small and indolent, further improvement of hematologic response may be achieved by consolidation strategies which may include high dose melphalan with autologous stem cell transplantation (HDM-ASCT); however, toxicity is significant and only a minority of patients is eligible for HDM-ASCT. New targets may provide new opportunities to eliminate the residual clonal plasma cells. Anti-CD38 targeting monoclonal antibody daratumumab has shown activity in myeloma and in AL amyloidosis with minimal toxicity. Specifically in AL, recent data indicate that even a short course of daratumumab was able to induce hematologic responses in several patients with relapsed or refractory AL. Thus, daratumumab may be a unique treatment to improve the outcomes of patients with AL amyloidosis. The endpoint was improvement of response 1 month In order to evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, we administered 4 weekly infusions of daratumumab in consecutively treated patients at the Department of Clinical Therapeutics, Athens, Greece with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy. Patients that had not achieved a response to primary therapy were excluded and received full dose salvage therapy. All patients received consolidation with 4 weekly infusions of daratumumab 16 mg/kg with dexamethasone 20 mg. Pre-emptive therapy for IRR was given starting two days before the first infusion of daratumumab that included low dose steroids (equivalent of 16 mg of methylprednisolone), H1 & H2 inhibitors and montelukast. So far 17 patients (15 AL and 2 LCDD) have received daratumumab consolidation. Among patients with AL amyloidosis, median age is 67 (range and 73% were males, kidneys and heart were involved in 80% and in 73% respectively, baseline Mayo stage was 20%, 67% and 13% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients (13/15 of AL patients were lambda). Median time from start of first line therapy to daratumumab consolidation was 9 months and all patients had completed the planned therapy of bortezomib-based treatment. At the time of initiation of daratumumab, 16 patients were in VGPR and one in PR and the median level of dFLC was 12 mg/L, all had positive serum or urine immunofixation and in all patients next generation flow (NGF) according to Euroflow protocol was positive for the presence of MRD. Except for one patient, all the others received the planned 4 daratumumab infusion; the single patient that did not receive the planned therapy did so because of a severe infection that occurred 1 day after the first daratumumab infusion and was not considered daratumumab related. IRRs occurred in 3 patients and were mild (grade 1 in 2 and grade 2 in one patient); no IRRs occurred after the first infusion. One month after completion of consolidation with daratumumab, median dFLC dropped to 5 mg/L and 41% of the patients improved their response: 37.5% from VGPR to hemCR and the one patients with PR to VGPR. Notably, small IgGkappa bands were found in 4 patients at one month post daratumumab. Among those that achieved a CR after daratumumab, 50% became MRD negative by NGF; however, further follow up is needed for the evaluation of organ responses after consolidation. We conclude that consolidation with a short course of daratumumab can improve the depth of response in patients with AL or LCDD that have not achieved a hemCR after primary therapy. In addition, some patients may even achieve MRD negative disease status. We will further explore this strategy in a formal clinical trial with a longer duration of daratumumab therapy so that CR and MRD negative rates may improve further. Disclosures Kastritis: Prothena: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Novartis: Consultancy. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

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Once Weekly Subcutaneous Bortezomib, Cyclophosphamide, and Dexamethasone As Induction Therapy for All AL Amyloidosis

Blood ◽

10.1182/blood.v128.22.5813.5813 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5813-5813 ◽

Cited By ~ 2

Author(s):

Hashim Abbas ◽

Lisa A. Rybicki ◽

Frederic J. Reu ◽

Christy Samaras ◽

Mitchell R. Smith ◽

...

Keyword(s):

Research Funding ◽

Stem Cell Transplant ◽

Cleveland Clinic ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Probability Of Survival ◽

Hematologic Response ◽

High Dose Melphalan

Abstract High dose melphalan followed by autologous stem cell transplant is the standard of care for all transplant eligible AL amyloidosis patients. Due to medical insurance approvals and pre-transplant evaluation, treatment is delayed by months. Given that there are many patients who respond quickly to bortezomib based regimens, we have adopted a bortezomib based induction regimen in an attempt to prevent early progression or death due to amyloidosis. Materials and methods: All AL amyloidosis patients treated at the Cleveland Clinic who received bortezomib 1.3 mg/m2 subcutaneous, cyclophosphamide 300mg/m2 (dose cap at 500 mg) intravenous or oral, and dexamethasone 20 mg intravenous or oral (CyBorD) on day 1,8, and15, of a 28 day cycle were included in this analysis. Patient information was obtained from an institutional review board approved database and electronic medical record review. Hematologic response was assessed every 28 days. Transplant eligible patients who achieved early complete hematologic response (CR) completed up to 6 cycles of CyBorD followed by high dose melphalan and autologous stem cell transplant (ASCT). If there was no CR at the end of 2 cycles of therapy, patients underwent high dose melphalan and ASCT. Non- transplant eligible patients completed a planned 6 cycles of CyBorD. The primary outcome of the study was to assess overall survival (OS) of all AL amyloidosis patients by Kaplan-Meier estimate. The secondary outcomes were to assess the best hematologic response1, with CyBorD plus ASCT versus CyBorD alone and evaluate if any transplant eligible patients were unable to proceed to ASCT after receiving CyBorD. Results: With a median follow up of 30 months, patients who received CyBorD plus ASCT had a 92% probability of survival. Patients who received CyBorD alone had a 47 % probability of survival. All patients who were deemed transplant eligible at diagnosis underwent high dose melphalan and ASCT. The median NT-proBNP for patients who underwent ASCT was 305 pg/ml and for patients who were transplant ineligible was 6047 pg/ml. The best hematologic response in patients who received bortezomib based induction plus transplant was CR 71%, very good partial response (VGPR) 18%, stable disease (SD) 6%, and progressive disease (PD) 6%. Patients treated with CyBorD alone had a CR 56%, VGPR 6%, SD 19%, and PD 12%. Discussion: None of the transplant eligible patients were deemed transplant ineligible after the induction therapy. The OS was excellent for patients who underwent transplant. The percentage of CR in the transplant eligible patients compared favourably to historical reports of CR with ASCT alone. Only 12 % of patients undergoing ASCT failed to achieve a VGPR compared to 37% of patients with CyBorD alone. Certainly the transplant ineligible patients had severely compromised baseline cardiac function but despite that the probability of survival at 30 months was 47%. With this data, we plan to standardize bortezomib based induction AL amyloidosis treatment with a care path for the entire Cleveland Clinic health care system. Abbreviations: NT-proBNP (amino-terminal pro-B-type natriuretic peptide). References: 1. Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012 Dec 20;30(36):4541-9 Figure 1 Probability of survival for all AL amyloidosis patients treated with CyBorD. Figure 1. Probability of survival for all AL amyloidosis patients treated with CyBorD. Disclosures Reu: Takeda: Research Funding; Novartis: Research Funding; Signal Genetics: Consultancy; Celgene: Research Funding. Smith:Genentech: Honoraria; Abbvie: Research Funding; Spectrum: Honoraria; Celgene: Honoraria. Valent:Takeda: Speakers Bureau; Celgene: Speakers Bureau.

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A phase II trial of lenalidomide for patients with AL amyloidosis

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7524 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7524-7524 ◽

Cited By ~ 1

Author(s):

V. Sanchorawala ◽

D. G. Wright ◽

M. Rosenzweig ◽

K. T. Finn ◽

M. Skinner ◽

...

Keyword(s):

Plasma Cell ◽

Phase Ii ◽

Phase Ii Trial ◽

Performance Status ◽

Underlying Disease ◽

Al Amyloidosis ◽

Severe Fatigue ◽

Starting Dose ◽

Grade 3 ◽

Age Range

7524 Introduction: A phase II trial was designed to evaluate the toxicity and response rate of lenalidomide (Revlimid, CC-5013), alone and in combination with dexamethasone in patients with AL amyloidosis. Patients with this plasma cell disorder have organ dysfunction that makes them more susceptible to drug toxicity. Methods: Planned enrollment, 35 patients. Regimen: 3 cycles of lenalidomide at 25 mg/d for 21d, with dexamethasone 10 mg bid for 4 days, 3 times a month, every other month, for those patients not responding to lenalidomide alone. Toxicity and responses were evaluated after 1, 3, 6, 9, and 12 months of treatment. Hematologic responses were based upon qualitative and quantitative measures of clonal plasma cell disease. Organ responses were scored according to published criteria. Results: 24 patients have been enrolled to date, age range is 47–76, M:F 18:6, κ:λ 7:17. Organ involvement: 75% renal, 38% cardiac, 18% hepatic or gastrointestinal, 17% neuropathy, 13% soft tissue or lymph node. 22 had been treated previously, and 12 had undergone treatment with HDM/SCT. After none of the first 6 patients tolerated 3 treatment cycles at 25 mg/day, the starting dose was reduced to 15 mg/day. A total of 112 cycles have been administered (1–14 cycles per patient). 2 patients were removed from study because of rashes; one because of gout and severe fatigue; one by choice; and one patient died in the first treatment cycle, apparently due to complications of the underlying disease. Grade 3 toxicities observed included fatigue (33%), hypoalbuminemia (29%), worsening performance status (29%), neutropenia (21%), rash (21%), dizziness (13%), gout (13%), dyspnea (8%), muscle weakness (8%), and pneumonia (8%). One patient (4%) had a DVT on lenalidomide and dexamethasone. 8 out of 13 have had a measureable hematologic response, of which 3 were complete or near complete. 8 patients had elevated free light chains (FLC) with a skewed κ:λ ratio, and 4 of these had ≥50% reduction in FLC level. 4 of 14 patients with proteinuria improved. Conclusion: Lenalidomide is reasonably well-tolerated in patients with AL amyloidosis, and alone or in combination with dexamethasone, can induce excellent hematologic responses and improvement in organ disease. No significant financial relationships to disclose.

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