Overall Hematologic Response Rate Research Articles

Outcomes of therapeutic plasma exchange for the treatment of patients with multiple myeloma cast nephropathy.

Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi-institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p=0.006), and achievement of ≥VGPR (OR 21.7 p<0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p=0.09). With a median follow-up of 36.4months, the median overall survival (OS) was 11months. On multivariable analysis, achievement of renal response (hazard ratio [HR]0.3, p<0.0001) and newly diagnosed disease (NDMM; HR 0.43, p=0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab-based regimens had a trend for better OS (p=0.15), compared to other regimens, but the difference was not significant. At the end of follow-up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab-based therapies showing promise.

Belantamab Mafodotin in Relapse/Refractory AL Amyloidosis- Real-Life Multi-Center Experience

Introduction: Bortezomib and daratumumab revolutionized the therapy for AL amyloidosis (AL). However, relapsed/refractory AL resistant to both drugs is an unmet clinical need, with limited options due to the frailty of these patients and paucity of prospective data. The safety profile and efficacy of belantamab mafodotin (BLM) in multiple myeloma (MM) are well known. In contrast, published data for AL are currently limited to case series of 6 (Zhang, Ann Hematol. 2022) and 12 patients only (Khwaga, Blood Cancer J. 2022). Here, we report a multicenter real-world data on 12 AL patients treated with BLM and compare these to the prior reports. Methods: We retrospectively identified all AL amyloidosis patients who received BLM outside a clinical trial, between Feb 2020-Sep 2022. The diagnosis, staging, hematologic and organ responses and progression of AL were evaluated according to consensus criteria. Event-free survival (EFS) was defined as the time from the first day of BLM administration to hematologic progression or therapy change for inadequate response or death. Results: Twelve AL patients from 5 centers in Israel and Italy were included. The median age at BLM initiation was 66 y (range 54-70). The most common FISH aberrations were 1q gain in 8 patients (67%) and t(11;14) in 5 (42%). All patients except one had cardiac involvement (92%) and 9 (75%) had renal involvement. The median number of prior lines of therapy was 3 (range 2-9). All patients previously received bortezomib, an alkylator and daratumumab, 11 (92%) received lenalidomide, 10 (83%) received pomalidomide and 9 (75%) underwent prior autologous transplant. Seven patients (58%) had Eastern cooperative oncology group performance status (ECOG-PS) of at least 2 at BLM initiation and half of the patients had AL Mayo stage of at least 3a. Most patients (10/12) received BLM as a single agent at 2.5mg/kg q3 weeks. The overall hematological response rate (ORR) to BLM was 75% (9/12), including 5 patients with complete response, 3 with very good partial response, and 1 with partial response (Figure 1). Detailed biomarker-based evaluation of organ responses was missing in many patients, yet, of 4 evaluable patients, 3 cardiac responses were observed. An additional patient had marked clinical improvement of heart failure. Four renal responses (out of 5 evaluable patients) and 2 hepatic responses (out of 2 evaluable) were also observed. With a median follow-up of 13.0 months (m) from initiation of BLM therapy (range 1.1-33.8m), the median EFS was 22.3m and the median OS was 28.8m. At data cutoff 6/12 (50%) were still on therapy, 9/12 patients (75%) were alive, all 3 deaths were due to heart disease. Seven patients (58%) had at least one grade 3 toxicity, included mostly infections/corneal toxicity. Apart from one event of grade 3 thrombocytopenia, there were no grade ≥3 hematological toxicities. No grade 4/5 toxicities were observed. Most patients (10/12, 83%) had corneal toxicity (6 patients- grade 1-2; 4 patients- grade 3), and dose reductions/delays were frequent (4/12 and 6/12, respectively). However, 7/10 patients with corneal toxicity improved overtime, no permanent visual disabilities were observed and only one patient stopped BLM due to keratopathy. Discussion: While BLM provides an ORR of 30-45% in triple-refractory MM patients, it might have a greater efficacy in AL patients. The ORR in our heavily pre-treated AL patients, as well as in other studies (2 small, retrospective + preliminary results of the EMN27 prospective study (Kastritis, EHA conference 2023) approached 60-83%, and the EFS was also encouraging. This difference may be attributed to the lower burden of disease in AL compared to MM. Alternatively, AL plasma cells may be more sensitive to BLM, in a mechanism that still merits further exploration. Corneal toxicity was similar to what was seen in MM, and overall manageable. Hematological toxicity was significantly milder than that observed in MM, probably related to the better marrow reserve in AL. Conclusions: BLM, being an off-the shelf immune therapy, with acceptable toxicity even in frail patients, can be a valuable option in AL, with a high ORR, and a signal for durable responses and high-quality organ responses in these patients.

Efficacy of Short-Duration Alemtuzumab in T-Cell Large Granular Lymphocytic Leukemia: Potential for a Response-Adapted Strategy

Introduction T-cell large granular lymphocytic leukemia (T-LGL) is a chronic incurable malignancy where once refractory to immunosuppressive therapy, few treatment options and no optimal treatment consensus exists. Alemtuzumab, 10 milligrams (mg) intravenously (IV) administered daily for a total of 10 doses, has been shown to be effective for relapsed or refractory (R/R) T-LGL (Dumitriu, et al. Lancet Haematol 2016); however, it can be associated with severe infusion reactions and infections. Given the palliative nature of T-LGL-directed treatments and the increasing potential for toxicity with cumulative alemtuzumab exposure, we conducted a retrospective analysis to describe the efficacy and safety of abbreviated alemtuzumab regimens in R/R T-LGL patients. Methods We identified patients ≥18 years with R/R T-LGL who were treated with short-duration (defined as ≤ 5 doses) alemtuzumab between 2012 and 2022 from the University of Washington lymphoma database. Patients who received prior alemtuzumab were excluded. The primary endpoint was overall hematologic response rate (ORR). Secondary efficacy endpoints included hematologic response rate at 3 and 6 months, rate of transfusion independence, progression-free and overall survival. Safety endpoints included rate of infusion reactions and infections, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation. Results Nine patients meeting criteria were identified (Table 1). Five patients received alemtuzumab 10 mg IV daily for 5 doses and 4 patients received alemtuzumab 10 mg IV weekly for 4 doses. Median age was 65 (range 34-81) years and the median number of prior regimens was 3 (range 1-5). All (100%) patients were refractory to immunosuppressive therapy. Seven (78%), 1 (11%) and 1 (11%) patients had unilineage, bilineage and trilineage cytopenias, respectively. Five patients (56%) had autoimmune comorbidities and five (56%) required periodic transfusions. No patients had myelodysplasia on bone marrow biopsy. Overall, 6 (67%) patients had a hematologic response with 2 patients achieving a partial response (PR) and 4 patients achieving a complete response (CR). ORR at 3 and 6 months was 56% and 44%, respectively. Two (40%) patients achieved transfusion independence. The 3 patients without a hematologic response were retreated with alemtuzumab 10 mg IV daily for 10 doses with 1 subsequently achieving a CR. At a median follow-up time of 7.2 (range 2.3-36.6) months, 3 out of 6 patients who achieved a response had disease relapse; 8 (89%) patients were alive and 1 had died from COVID-19 pneumonia. Among the 5 patients who received alemtuzumab at 10 mg daily for 5 doses, ORR was 40% with 1 patient achieving PR and 1 patient achieving CR. ORR at 3 and 6 months was 40% and 40%, respectively. One (20%) patient had an infusion reaction. Two patients (40%) had subclinical CMV viremia which resolved with valganciclovir. No cases of EBV viremia were noted. Four patients completed alemtuzumab at 10 mg weekly for 4 doses; ORR was 100% with 1 patient achieving PR and 3 achieving CR. Hematologic response rate at 3 and 6 months was 75% and 50%, respectively. Three (75%) patients relapsed at 3, 4 and 14.2 months, respectively; 2 were retreated 4-6 times with alemtuzumab 10 mg IV weekly for 2 to 6 doses each time, with both achieving hematologic responses with each course of treatment. One (25%) patient experienced an infusion reaction. No cases of CMV or EBV viremia were noted. Conclusions Short-duration alemtuzumab is effective and well tolerated in R/R T-LGL with responses observed in 67% overall and no cases of CMV viremia detected in the weekly dosing group. Alemtuzumab given at 10 mg IV weekly for 4 doses or until a response is noted followed by retreatment upon relapse was particularly effective; this abbreviated, response-adapted alemtuzumab strategy should be prospectively explored in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anti-Human T Lymphocyte Porcine Immunoglobulin Combined with Cyclosporine As First-Line Immunosuppressive Therapy for Severe Aplastic Anemia in China: A Large Single-Center, 10-Year Retrospective Study

Immunosuppressive therapy (IST) based on antithymoglobin (ATG) and cyclosporin (CsA) is the first-line treatment for severe aplastic anemia (SAA) patients who are ineligible for transplantation. Horse ATG is recommended as the standard preparation for first-line immune suppression in SAA, but it has been unavailable in China since the year 2000. The anti-human T lymphocyte porcine immunoglobulin (p-ATG, provided by Yujin Bio-Pharma Wuhan CNBG Co., Ltd., Wuhan, China) was made available in 1983 and approved for the treatment of aplastic anemia by the Sino Food and Drug Administration in 2004. It is a commonly used ATG preparation in IST for SAA in China since 2009. To date, only a few small retrospective cohort studies reported that p-ATG combined with cyclosporine (CsA) is a useful immunosuppressive regimen for SAA in China. This study retrospectively analyzed the data of 1023 consecutive patients diagnosed with SAA that aimed to evaluate the early hematologic response and long-term outcomes of this large cohort of patients with SAA who received p-ATG plus CsA as first-line therapy from 2010 to 2019. Patients received p-ATG for 5 consecutive days (day 1-5), at a dose of 20 mg/kg/day. And CsA was administered orally from day 1 of p-ATG treatment at two separate doses starting from 3 to 5 mg/kg/day and adjusted to maintain the trough concentration at 150-250 ng/ml and the peak concentration at 800-1000 ng/ml. One thousand twenty-three aplastic anemia were included in this study, with a median age of 24 (4-75) years, with 500 males and 473 females. The median follow-up was 57.2 months (3 days-137.5 months). Twenty-nine patients died within 3 months after IST, with an early death rate of 2.8% (29/1023); the median death time was 0.9 (0.1-2.9) months. The overall hematologic response rate (ORR) was 40.6% (415/1023) at 3 months, including 5.9% (60/1023) of patients with CR. The ORR was 53.2% (544/1023) at 6 months, including 13.5% with CR. Of the 395 patients who did not respond at 6 months, 26.1% (103/395) had an overall response at 12 months without any rescue treatment (10 had a CR, 93 had a PR). By the last follow-up, 9.2% (64/697) of the patients had experienced a relapse. The 5-year cumulative incidence of relapse was 9.0% [95% confidence interval (CI), 4.2 to 16.0%]. The 5-year cumulative incidence of clonal evolution was 4.5% (95% CI, 1.4 to 10.6%). The 5-year cumulative incidence of hPNH was 4.7% (95% CI, 1.2 to 12.4%). In patients with PNH clones at diagnosis, the 5-year cumulative incidence of hPNH was 22.5% (95% CI, 10.1 to 37.8%). The 5-year OS rate was 83.7% (95% CI, 81.1 to 86.0%). The 5-year event-free survival rate was 50.4% (95% CI, 47.1 to 53.5%). In conclusion, p-ATG combined with CsA for the treatment of AA is effective and safe, and p-ATG can be used as an alternative ATG preparation for the standard IST regimen in areas where h-ATG is not available.

Ivosidenib Monotherapy Is Effective in Patients with IDH1 Mutated Myelodysplastic Syndrome (MDS): The Idiome Phase 2 Study By the GFM Group

Background: Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mutant IDH1 approved in the US for adult patients with unfit or relapse/refractory AML with IDH1 mutation. Little is known on its efficacy in patients with IDH1 mutated MDS. Here we report interim results of a Phase 2 study evaluating safety and efficacy of IVO in three different cohorts of MDS patients: Higher risk MDS having failed azacytidine (AZA) (cohort A, n=29), untreated higher risk MDS without life threatening cytopenias (ie ANC < 500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom,) as a first line treatment (cohort B, with the addition of AZA in non-Responders after 3 cycles, n=29) and lower risk MDS having failed EPO (cohort C, n=10). (ClinicalTrials.gov NCT03503409).Methods: Subjects enrolled in cohort A, B or C received continuous 28-day cycles of IVO - 500 mg orally QD. In cohort B, AZA (75 mg/m2/d x 7 days, SC) was added to IVO after 3 cycles, only in the absence of IWG 2006 response (absence of CR, PR or HI). The primary endpoint was overall hematological response rate (ORR) at 3 and 6 months (including CR, PR, stable disease with HI according to IWG 2006). All responders allowed to continue treatment until loss of response. Secondary endpoints included safety, duration of response, EFS, overall survival and translational project evaluating the role of biomarkers on response. We report the preliminary results on the first 26 pts enrolled.Results: At data cut off (6/15/2021), 32 patients had been enrolled, including 26 who were evaluable for the primary endpoint. 13, 11 and 2 were enrolled in cohort A, B and C respectively. Median age was 76 years and 50% were female. WHO was MDS-MLD, MDS-EB1, MDS-EB2, CMML and low blast count AML in 2, 2, 12, 1 and 9 patients respectively. IPSS-R was low, intermediate, high and very high in 2, 6, 5 and 13 resp. IDH1 mutation was p.R132C in 15 patients, p.R132H in 7, p.R132G/S in 3 and not specified in 1.The ORR was 69% (18 patients) including 12 CR (46%), 1 PR and 5 HI. Most patients achieved response after 3 cycles (17/18). Response was achieved in 7 (54%), 10 (91%) and 1 (50%) in cohort A, B and C respectively. Moreover, CR was achieved in 3, 8 and 1 in cohort A, B and C respectively. In cohort B, AZA was added to IVO in one patient after 3 cycles, without additional response.With a median follow up of 9.1 months, the median duration of response of the 18 responders was 7.4 months, 9 of them lost their response, and two had died without loss of response (from bleeding and after HSCT, respectively). IPSS-R was the only prognostic factor of response after 6 cycles.At data cut off, 12 patients had progressed (9 in cohort A, 2 in cohort B and 1 in cohort C) and 11 (42%, 10 in cohort A and 1 in cohort C) patients had died, mostly of relapse/progression (n=5/11), infection in 1, suicide in 1, hemorrhage in 1 and other unrelated causes in 3.Median overall survival was 14 months in the whole cohort, 7.7 and not reached in cohort A and B resp.The most common treatment-related serious adverse event (SAE) was differentiation syndrome (4/5), one died and three resolved without sequelae. One patient had febrile neutropenia related to IVO, resolved without sequelae.Conclusion: IVO was well tolerated in MDS patients with significant responses in all the cohorts. With a response rate of 91%, IVO was particularly effective in treatment naïve higher risk MDS patients with IDH1 mutations (cohort B). These encouraging preliminary results have to be confirm in more patients. The IDIOME study is still ongoing, and molecular monitoring results of IDH1 mutations will be presented. DisclosuresSebert: BMS: Consultancy; Abbvie: Consultancy. Cluzeau: Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses. Stamatoulas Bastard: Pfizer: Other: Travel Support; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Ades: Abbvie: Honoraria; Takeda: Honoraria; Novartis: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding.

Patients with relapsed/refractory hairy-cell leukemia.

BackgroundHairy cell leukemia (HCL) is a rare chronic B‐cell neoplasm with good long‐term prognosis. First and second‐line therapies include purine nucleoside analogues (PNAs) and rituximab, but until recently, limited alternative options were available for patients with two or more relapses.AimThe aim of this study is to describe our real‐life experience with HCL patients in third and fourth‐line therapies.Methods and ResultsData from 49 HCL patients with two or more relapses, including 16 patients with three or more relapses, were collected from the French retrospective HCL cohort covering the period from 1980 until 2011. They were analyzed to assess hematological response, relapse free survival (RFS) and overall survival (OS) after third (L3) and fourth line (L4). The median age at diagnosis was 53 years. PNAs were the most frequently used treatments. As L3 therapy, 29 patients received PNAs (66%) and 15 (34%) other treatments (rituximab [11%] or interferon [7%] alone or in combination [16%]). The distribution of L4 treatments was similar. The overall hematological response rate (OHRR) after L3 was 97% (complete hematological response 86%) with a 40% five‐year cumulative incidence of relapse (CIR), a median RFS of 104 months, and a median OS of 235 months. After L4, the OHRR was 94% with a two‐year CIR of fourth relapse of 27%. Eleven secondary cancers (5‐year cumulative incidence of 12%) were diagnosed in 10 patients. Patients with ≥2 relapses experience frequent further relapses, with increasingly shorter time to next treatment as the number of treatment lines increases. Furthermore, treatment strategies are associated with substantial toxicities.ConclusionAll these points lead to the need for novel treatments.

Primary Results from the Phase 3 Tourmaline-AL1 Trial of Ixazomib-Dexamethasone Versus Physician's Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL)

Primary Results from the Phase 3 Tourmaline-AL1 Trial of Ixazomib-Dexamethasone Versus Physician's Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL)

Results of a Phase 2 Trial of High Dose Lenalidomide Monotherapy in Patients with Relapsed/Refractory Higher-Risk Myelodysplastic Syndromes or Acute Myeloid Leukemia with Trilineage Dysplasia

Background: Outcomes of patients (pts) with refractory and relapsed higher-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia with trilineage dysplasia (AML-TD) are dismal and therapeutic options are limited. Two phase 2 clinical trials reported clinical benefit using single agent high dose (50 mg) lenalidomide in elderly pts with untreated AML with and without deletion 5q (del5q), but this approach has not been formally studied in pts with AML-TD or HR-MDS who were refractory or relapsed following frontline therapy.Methods: This single-arm phase II study conducted at Johns Hopkins University enrolled pts with HR-MDS defined as IPSS high and INT-2 and pts with AML-TD regardless of karyotype. Pts received 2 cycles of lenalidomide at 15 or 50 mg daily on days 1-28 out of 42-day cycles; the protocol was originally designed at 15 mg/day, but dose was increased to 50 mg/day upon publication of safety/efficacy data in AML. Up to 3 weeks off treatment were allowed for count recovery but dose reductions for hematologic toxicity were not allowed. Responses were evaluated using the International Working Group 2006 criteria (IWG-2006). Pts with stable disease were allowed to receive 2 additional cycles. Responding pts were allowed to continue to receive drug until progression. The primary endpoint was overall hematologic response rate (ORR) following administration of 2-4 cycles of lenalidomide. Toxicities were graded according to CTCAE 3.0 criteria. Overall survival (OS) was calculated from first dose of lenalidomide and estimated by Kaplan-Meier (KM) methods. The study protocol was approved by Johns Hopkins Institutional Review Board. The study was sponsored by Celgene Corporation.Results: Twenty seven pts were enrolled between July 2009 and March 2014, of whom 9 received the 15 mg dose and 18 received the 50 mg dose. Median age was 72 years (range, 47-88 years); 76% were ≥65 years; 16 pts had HR-MDS and 11 had AML-TD. No pt had isolated del5q but 2 pts had del5q as part of complex karyotype; 41% had poor-risk karyotypes. Median bone marrow blast percentage was 15% for the entire cohort (range, 2-90%) and 40% for AML-TD pts. Median platelet count was 37×10⁹/L (range, 3-293×10⁹/L), and 63% of pts had platelet count of 50 or lower. Median white blood cell count was 2.4×10⁹/L (range, 0.5-6.4×10⁹/L) while median hemoglobin was 9.2 gm/dL (range, 6.7-14). Median number of prior regimens was 1 (range, 1-4). Median follow-up on study was 67 days (range, 9-245). Among the 9 pts who received 15 mg dose, 5 (55.6%) completed ≥2 cycles, none achieved an objective response, and none had grade 3 or 4 non-hematologic toxicity that was likely related to lenalidomide. Among the 18 pts treated at 50 mg dose, all had grade 3 or 4 non-hematologic toxicity, most commonly neutropenic infections, and only 7 pts (38.9%) completed ≥2 cycles of therapy. Among 18 pts treated on the 50 mg dose, ORR was 11% (both partial responses) and therefore the study was stopped due to futility. Both responders had AML-TD; one had normal karyotype and the other had monosomy 7. Overall, 30- and 60-day mortality rates were 14.8% and 29.6%, respectively. Median OS for the entire cohort [Figure 1] was 114 days (range, 15-841). Five pts (18.5%) survived ≥1 year; of those 1 pt got salvage low dose cytarabine; another underwent bone marrow transplantation, whereas the others chose supportive care alone.Conclusions: High dose lenalidomide(50 mg daily) administered on a 28/42-day cycles in pts with relapsed/refractory HR-MDS or AML-TD is poorly tolerated and associated with signficant toxicity and minimal activity. Further exploration of high dose lenalidomide in pts with AML-TD and HR-MDS should probably employ an intermittent dosing schedule and focus on intensive chemotherapy-ineligible untreated pts with AML. [Display omitted] DisclosuresOff Label Use: Use of high dose lenalidomide for higher risk MDS and AML. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Long-Term Outcome of a Phase 1 Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib at the Recommended Phase 3 Dose (RP3D) in Patients (Pts) with Relapsed or Refractory Systemic Light-Chain (AL) Amyloidosis (RRAL)

Long-Term Outcome of a Phase 1 Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib at the Recommended Phase 3 Dose (RP3D) in Patients (Pts) with Relapsed or Refractory Systemic Light-Chain (AL) Amyloidosis (RRAL)

Safety Profile Of Bortezomib Impacts Survival Of Cardiac AL Amyloidosis

BackgroundLight chain amyloidosis (AL) is characterized by a median overall survival (OS) from diagnosis of approximately 3 years, but with clinically overt cardiac involvement this is reduced to 1 year. Bortezomib (B) has shown great promise in the treatment of AL, especially of cardiac involvement. However, efficacy might be hampered by severe safety issues with use of B, primarily of neuropathy type. We sought to study the prognostic impact of the safety profile of B in AL with attention to cardiac involvement. MethodThis study has included 27 patients with AL, of these 18 had cardiac and 9 kidney but no cardiac involvement. AL was diagnosed as outline in international consensus criteria, as to the hematologic and organ responses. B was given IV twice weekly at the starting dose of 1.3 mg/m², in combination to weekly cyclophosphamide in 13 patients (52%). ResultsThe median age was 63, sex ratio was 18/9, all cardiac AL had Mayo Cardiac Stage III but 3, and none in patients with no cardiac AL. 70% were at diagnostic. Seven patients died during the first month, all of them but one had cardiac AL. We then looked at the safety profile of B in the studied population, and found that 25% and 75% experienced some degree of hematotoxicity in cardiac and in no cardiac AL (p=NS). The non hematology toxicity rate was 62% and 38%, respectively (p=NS). 26% of patients needed dose reduction of B and 33% dose interruption of B in the study before cycle 4, all related to non hematological toxicity of neuropathy, fatigue and GI AEs; and was similar in cardiac as compared to no cardiac AL.The overall hematologic response rate (ORR) was 56% and at least VGPR (with >90% decrease in difference between involved/uninvolved light chain) 41%. The responses were 56% and 39% in cardiac AL, similar to patients with no cardiac involvement (56% and 44%), respectively. The median duration of response was 13 months overall, 10 and 20 months in cardiac and in no cardiac AL, respectively (p=NS). Non hematological toxicity did not impact the response rate or the duration of response.With a median follow-up of 41 months from start of B, 70% relapsed and 59% died in the study as a whole, and 67% and 67% in the cardiac group, respectively. The median time to progression was 20 (95CI 4;35.5) months as a whole, and 13 (9;17) months and 20 (0;43) months in cardiac and in no cardiac AL (p=NS). The median OS was not reached in the cohort as a whole and in patients with no cardiac involvement, but was 5 months in cardiac AL (p=NS); the estimated 4-year OS was 55%, 62% and 50%, respectively. Interestingly, all cardiac AL that survived beyond 6 months remain alive at F-up date. Several variables negatively impacted survival in univariate analysis in the group with cardiac AL, including decreased LVEF (p=0.025), NYHA greater than 2 (p=0.007),Mayo Cardiac Stage III (p=0.028), no hematological (p=0.002) and no organ responses (p=0.05), occurrence of non hematological toxicity (p=0.002) with the consequence of dose reduction of B (p=0.09) and dose interruption of B (p=0.04).In multivariate analysis, independent variables that impacted survival were hematological response (OR = 5.1, 95%CI = 1.5-18; p = 0.011) and non hematological toxicity (OR = 3.6, 95%CI = 0.8-14; p = 0.05). ConclusionBortezomib is a very rapid and effective therapy for AL particularly of cardiac involvement. However, patients may develop severe side effects with Bortezomib that preclude efficacy of Bortezomib given IV, and consequently impact negatively survival. This data favours use of sub cutaneous Bortezomib in AL although not validated in this indication yet. Disclosures:Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria.

Bortezomib-Containing Regimens in the Treatment of AL Amyloidosis: A Single Center Experience

Abstract 4614Treatment of patients (pts) with systemic AL Amyloidosis remains challenging and organ dysfunctions improve in not more than 1/3 of cases with standard treatment. Bortezomib has been reported to have activity in this disease, where the misfolded protein may render the amyloidogenic plasma cells particularly vulnerable to proteasome inhibition.To evaluate the feasibility and efficacy of Bortezomib, we report our single center experience with Bortezomib-containing regimens in pts with AL Amyloidosis. Hematologic responses and functional organ responses were evaluated according to the 2005 International Society of Amyloidosis criteria (Gertz et al, Am J Hematol 2005). Complete hematologic response (CR) was defined as normalization of the free light chain ratio with no evidence of a monoclonal protein by immunofixation and partial response (PR) as a 50% reduction in M-spike or absolute light chain level; moreover, dFLC (difference between involved and uninvolved free light chain) < 40 mg/L defined a very good PR (VGPR). A cardiac response was also defined by NT-proBNP criteria (>30% and >300 mg/L decrease in pts with baseline NT-proBNP > 650 mg/L).Since May 2010, 21 consecutive pts with AL Amyloidosis were treated with Bortezomib-containing regimens at our center: Bortezomib-Dexamethasone (Vel-D), 5 pts; Cyclophosphamide-Bortezomib-Dexamethasone (CyBOR-D), 14 pts; Bortezomib-Melphalan-Prednisone (VMP),2 pts. Median age was 62 years (43-74). Fifteen pts were treated upfront, while 7 had refractory or relapsed disease after several lines of therapy. According to the cardiac staging system based on NT-proBNP and troponin I, 6 (29%) pts were stage 1, 9 (42%) stage 2 and 6 (29%) stage 3. At the time of this report 9 pts, still on treatment, have received less than 4 cycles and are not yet evaluable for response. Twelve pts received a median of 5,5 cycles (range, 4–8) and were analysed for outcome. Five received Vel-D, 5 CyBOR-D and 2 VMP. Eight were treated upfront and 4 after previous treatment (including ASCT in 3). Ten (83%) had renal, 6 (50%) cardiac, 2 (17%) soft tissue, 3 (25%) nerve, 2 (17%) gastrointestinal tract and 1 (8%) liver involvement. Four pts (33%) achieved hematologic CR, 3 (25%) VGPR and 3 (25%) PR (overall hematologic response rate (ORR) 83%), with no difference in ORR between Vel-D and CyBOR-D. One pt had a stable disease and 1, treated for second relapse, had progressive disease and died. Median time to response was 2 months (2-4). One pt underwent HD-MEL after PR with Vel-D and 3 pts had peripheral blood stem cells collected (soon after diagnosis (2) and after initial response (1)) and cryopreserved (to perform ASCT if unsatisfactory response or relapse). Four of eight evaluable pts (50%) had a renal response and 4/6 (66%) had a cardiac response. Hematologic toxicity was negligible; 6 pts had significant extra-hematologic complications, including 3 heart failure, 2 interstitial and 1 bacterial pneumonia, 1 Staph. sepsis, 1 H1N1 virus infection, 1 CMV reactivation, 1 grade 3 neuropathy and 1 grade 3 diarrhoea. No pts died because of toxicity. CyBor-D was apparently better tolerated.In this unselected series of systemic AL Amyloidosis, Bortezomib-containing regimens produced rapid hematologic response in the great majority of pts, with and an high rate of organ response. Bortezomib represents a major advance in the clinical management of this disease. Disclosures:No relevant conflicts of interest to declare.

G-CSF Increases Hematological Response among Patients with Myelodysplasia Treated with Azacitidine.

Rationale: Myelodysplastic syndrome (MDS) is characterized by peripheral blood cytopenia, a major cause of morbidity and mortality. Two current treatments that may ameliorate cytopenia in MDS are azacitidine (aza) and hematopoietic growth factors. When used alone in MDS, erythropoietin (epo) and G-CSF are reported to increase the hemoglobin level and the neutrophil count, respectively. Additionally, epo and G-CSF may work synergistically to improve anemia and neutropenia. This study examined whether the combination of growth factors and aza would be more effective than aza alone for the treatment of MDS.Methods: We identified 86 MDS patients treated at our institution who received an average of 10.8 cycles of aza. Forty-nine (49) of these patients also received either epo, G-CSF or both during the course of their aza treatment, while 37 did not receive hematopoietic growth factors. These 2 groups did not differ significantly either in number of cycles of aza received (p=0.34) or FAB MDS subtype (p=0.50). Hematological responses were tabulated by International Working Group criteria and compared using chi-square statistics.Results: Patients treated with aza alone had a 51% (19/37) overall hematological response rate (OHR). Patients who received aza + epo (A + E) had a 50% (6/12) OHR and when compared to aza alone (A), was not statistically different (p=0.9). Patients who received aza + G-CSF +/− epo (A + G +/− E) had an 84% (31/37) OHR versus 51% (25/49) in patients who did not receive G-CSF (A +/− E) (p=0.003). When the group A + G +/− E was compared to A +/− E there was a statistically significant difference in favor of A + G +/− E in erythroid (77% vs. 37%; p=0.001) and platelet (72% vs. 47%; p=0.04) response, but no difference in neutrophil response (71% vs. 67%; p=0.9).Conclusion: In patients with MDS treated with aza the addition of G-CSF improved OHR, erythroid and platelet response. Surprisingly, neutrophil response was not improved. The biological basis for these observations suggests an effect upon erythroid and megakaryocytic lineages. We postulate that G-CSF may have an anti-apoptotic effect as has been previously demonstrated when used in combination with epo.