Hematologic Response Rate Research Articles

Rapid and Deep Hematologic Responses Are Associated with Improved Major Organ Deterioration Progression-Free Survival in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Background: As immunoglobulin light chains present in AL amyloidosis are considered to be toxic to involved organs, especially the heart, rapid and deep hematologic remission with reduction of these light chains with frontline therapy may be crucial to improving long-term clinical outcomes. ANDROMEDA (NCT03201965) is the first phase 3 study in this patient population to evaluate major organ deterioration progression-free survival (MOD-PFS), a composite endpoint of time to end-stage cardiac disease (requiring cardiac transplant, left ventricular assist device, or intra-aortic balloon pump); end-stage renal disease (requiring hemodialysis or renal transplant); hematologic progression per consensus guidelines1; and death. Here, we report the impact of early and deep hematologic responses on MOD-PFS. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study of patients with newly diagnosed AL amyloidosis who received cyclophosphamide, bortezomib, and dexamethasone (VCd) ± daratumumab subcutaneous (DARA SC; DARA 1800 mg coformulated with recombinant human hyaluronidase PH20 in 15 mL). Key eligibility criteria were newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Disease evaluations occurred every 4 weeks during Cycles 1-6. Hematologic responses were adjudicated by an Independent Review Committee. Landmark analyses for response were performed at 1 and 3 months (± 7 days). Analyses of hematologic responses and MOD-PFS were performed on the intent-to-treat analysis set. Patients without a baseline or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between groups. The proportions of patients with heart and kidney involvement were 71% and 59%, respectively. Median follow-up was 11.4 months (range, 0.03-21.3+). For the 1- and 3-month landmark analysis, hematologic response was available for 356 and 289 patients, respectively. Hematologic response rates by treatment group at 1 and 3 months are shown in the Table. MOD-PFS was longer in patients with complete response (CR)/very good partial response (VGPR) at 1 and 3 months vs patients with lower levels of response (Figure). CR/VGPR at 1 and 3 months was associated with reduced risk of death or major organ deterioration in a multivariate analysis adjusting for baseline difference between involved and uninvolved free light chains and cardiac stage, (HR: 0.399, P=0.0006 and HR: 0.262, P=0.0003, respectively). At 1 and 3 months, cardiac and renal response rates were higher in those who achieved early and deep hematologic responses (CR and VGPR). Conclusions: CR/VGPR at 1 and 3 months was associated with a reduced risk of major organ deterioration and death in patients with newly diagnosed AL amyloidosis. These data confirm that initial therapy that achieves rapid and deep hematological responses is essential to improving long-term outcomes in AL amyloidosis. Reference 1. Comenzo RL, et al. Leukemia. 2012;26(11):2317-25 Disclosures Wechalekar: Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory; Celgene: Honoraria; Takeda: Honoraria, Other: Travel. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Comenzo:Caleum: Consultancy; Unum: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Jaccard:Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding; Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Kastritis:Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Phase 2 Trial of Ixazomib, Cyclophosphamide and Dexamethasone for Treatment of Previously Untreated Light Chain Amyloidosis

Phase 2 Trial of Ixazomib, Cyclophosphamide and Dexamethasone for Treatment of Previously Untreated Light Chain Amyloidosis

The Italian Medicines Agency Prospective Registry of Bortezomib-Based Treatment in AL Amyloidosis

Background: There is no licensed therapy for light chain (AL) amyloidosis; however, bortezomib (B) is considered standard upfront treatment. Existing data on safety and efficacy of B in AL amyloidosis derive from clinical trials and retrospective series from few referral centers and only partly reflect real-world practice. In 2011, the Italian Medicines Agency (AIFA) started a program to grant access to upfront B to patients with AL amyloidosis. Treated patients had to be enrolled in an online registry and prospectively followed during therapy. We report the treatment experience in this real-world setting. Methods: AL amyloidosis diagnosis required tissue typing with mass spectrometry or immuno-electron microscopy. Patients samples could be sent to the Pavia specialized center for typing, but patients were not treated under the supervision of the referral center. Subjects with multiple myeloma were excluded. Variables were collected at baseline and hematologic and cardiac responses were assessed after 8 weeks (approximately 2 cycles) according to the International Society of Amyloidosis criteria. The cox proportional model has been adopted to assess the risk of treatment discontinuation according to the baseline characteristics. Results: A total of 754 patients were treated between May 2011 and October 2019 and 605 were included in the analysis. Most common reasons for exclusion were retrospective data collection (45%), and incomplete data set (31%). Median age was 67 years (range 26-89 years). 82% of patients had heart involvement. Cardiac stage was I in 18% of subjects, II in 45%, IIIa in 21%, and IIIb, in 16%. Sixty-seven percent of patients had renal involvement, and 13% and 14% had severe (glomerular filtration rate [eGFR] between 30 and 15 mL/min) and end-stage (eGFR <15 mL/min) renal insufficiency, respectively. Differential free light chain level (dFLC) was >180 mg/L in 41% of cases. Bortezomib was administered with dexamethasone (D) alone in 41% of patients, with cyclophosphamide and D (CyBorD) in 44%, and with melphalan and D (BMDex) in 13% of subjects. Other combinations were used in 2% of patients. In the overall population, the initial dose of B was attenuated (<1.3 mg/m2) in 22% of patients. The proportion of patients receiving attenuated dosage was higher in stage III patients (38%). Fourteen percent of subjects required B dose reduction during therapy, while B dosage could be increased in 7% of patients who started at a reduced dose. A twice-weekly B schedule at treatment initiation was used in 22% of all subjects and in 16% of stage III patients. Fourteen percent of patients initially treated with the twice weekly schedule needed to be shifted to the once weekly schedule. After 8 weeks (approximately 2 cycles) the overall hematologic response rate was 58% (CR 3%, VGPR 20%) and cardiac response was attained in 14% of patients. The median number of cycles performed was 3 (range 1-9), median duration of monitored treatment was 4.3 months. Treatment was discontinued during monitoring due to achievement of satisfactory response or completion of maximum (9) allowed number of cycles in 3% of cases, progression in 14%, death in 8%, and toxicity in 1% of patients. The cause of discontinuation was defined as independent of drug and disease in the remaining 25.1% of subjects. Risk of treatment discontinuation was lower in patients who could tolerate a 1.3 mg/m2 dose of B from cycle 1 (HR 0.70, 95%CI 0.54-0.91). Second-line therapy with immunomodulators (most commonly lenalidomide) was started in 14% of patients. Conclusions: Patients with AL amyloidosis start treatment at an advanced stage and early deaths are common. The rate of severe/end-stage renal failure was higher (27%) than expected, possibly indicating that these patients are less likely to be referred to specialized centers. Remarkably, outside referral centers B is commonly administered with D alone. Dose reductions are frequently applied, but dosage can be escalated during therapy. Response rates at 8 weeks are comparable to those reported in other large studies and early cardiac responses are possible. To the best of our knowledge this is the only study prospectively evaluating treatment with B in a real-world setting. Treatment registries under the supervision of regulatory agencies are precious tools to assess common therapeutic practice in rare disease, to evaluate candidate comparators for future trials, and to assess unmet medical needs. Disclosures Palladini: Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Milani:Janssen: Other: Speaker honoraria; Celgene: Other: Travel support; Pfizer: Other: Speaker honoraria. Nuvolone:Janssen: Honoraria. OffLabel Disclosure: Bortezomib in AL amyloidosis

A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients with Previously Treated AL Amyloidosis (SWOG S1702; NCT#03499808)

A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients with Previously Treated AL Amyloidosis (SWOG S1702; NCT#03499808)

Retroperitoneal Involvement of Light Chain Amyloidosis-Case Series and Literature Review

Retroperitoneal Involvement of Light Chain Amyloidosis-Case Series and Literature Review

Reduction in Absolute Involved Free Light Chain and Difference between Involved and Uninvolved Free Light Chain Is Associated with Prolonged Major Organ Deterioration Progression-Free Survival in Patients with Newly Diagnosed AL Amyloidosis Receiving Bortezomib, Cyclophosphamide, and Dexamethasone with or without Daratumumab: Results from Andromeda

Background: Systemic AL amyloidosis is characterized by the deposition of insoluble amyloid fibrils produced by light chains synthesized by clonal CD38+ plasma cells. Combining daratumumab (DARA) with bortezomib, cyclophosphamide, and dexamethasone (VCd) has demonstrated significantly improved outcomes in patients with AL amyloidosis. The classification of hematologic complete response (CR) in this disease is evolving, and the absolute reduction of the involved free light chain (iFLC) and the difference between iFLC and uninvolved free light chain (dFLC) are being recognized as very meaningful endpoints. Here, we present results from the ANDROMEDA study (NCT03201965) to demonstrate the impact of achieving deep reductions of iFLC and dFLC on major organ deterioration progression-free survival (MOD-PFS), a novel, key secondary endpoint in this study. Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease (serum monoclonal protein ≥0.5 g/dL by protein electrophoresis or serum free light chain ≥5.0 mg/dL with an abnormal kappa:lambda ratio or dFLC ≥50 mg/L), ≥1 involved organ, cardiac stage I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 subcutaneous [SC] weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every other week in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of FLC levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if iFLC<upper limit of normal.1-2 The following criteria for deep hematological response were evaluated: iFLC ≤20 mg/L regardless of FLCr3 and dFLC<10 regardless of FLCr.4 MOD-PFS is a composite endpoint defined as any one of the following events (whichever comes first): death; cardiac deterioration (requiring cardiac transplant, left ventricular assist device or intra-aortic balloon pump); end stage renal disease requiring hemodialysis or renal transplant; or hematologic progression per consensus guidelines.1 Analyses of deep hematological responses were performed on the intent-to-treat analysis set; patients without a baseline assessment or post-baseline assessment were considered non-responders. Descriptive statistics were used to summarize overall response rates. Kaplan-Meier curves were plotted for MOD-PFS by hematologic response status. Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and 65% of patients had ≥2 organs involved. The proportions of patients with heart and kidney involvement were 71% and 59%, respectively, and the proportions of patients with cardiac stage I, II, and IIIA were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). The rates of deep hematological responses by all criteria strongly favored the DARA-VCd treatment arm (Table). MOD-PFS was longer in patients achieving deep hematological responses by all criteria (Figure). In addition, the corresponding MOD-PFS was similar regardless of the hematological response criteria used. Conclusions: Regardless of the criteria used, the addition of DARA to VCd increased the rates of deep hematologic responses in patients with newly diagnosed AL amyloidosis, which, in turn, was associated with prolonged MOD-PFS. These results support the benefit of DARA in this patient population.

Subcutaneous Daratumumab (DARA SC) + Bortezomib, Cyclophosphamide, and Dexamethasone (VCd) in Asian Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: Subgroup Analysis from the Phase 3 Andromeda Study

Introduction: Systemic AL amyloidosis is a rare disorder of clonal CD38+ plasma cells characterized by deposition of insoluble amyloid fibrils leading to tissue damage and organ dysfunction. Currently, there are no health authority-approved treatments for AL amyloidosis, and standard of care (SoC) includes therapies developed for multiple myeloma (MM). DARA is a human CD38-targeting antibody for MM. Combining DARA with VCd improved outcomes for AL amyloidosis versus VCd alone in the phase 3 ANDROMEDA study. Here, we report a subgroup analysis of Asian patients (China, Japan, and Korea) from ANDROMEDA. Methods: Eligible patients had newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and no symptomatic MM. Patients were randomized 1:1 to receive DARA SC plus VCd (D-VCd) or VCd. All patients received bortezomib (1.3 mg/m2 SC QW), cyclophosphamide (300 mg/m2 PO or IV QW), and dexamethasone (40 mg PO or IV QW) for six 28-day cycles with or without DARA SC (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.) by injection QW in Cycles 1-2, Q2W in Cycles 3-6; after Cycle 6, patients continued DARA monotherapy as maintenance for up to 24 cycles (28-day cycles). Disease status was evaluated Q4W in Cycles 1-6 and Q8W after Cycle 7 until hematologic progression or major organ deterioration. The primary endpoint was overall hematologic complete response (CR) rate; key secondary endpoints included major organ deterioration progression-free survival (MOD-PFS), survival, and safety. MOD-PFS was defined as the time from randomization to any of the following events (whichever occurred first): death, clinical manifestation of cardiac or renal failure, or hematologic progression. Results: Among 388 randomized patients (D-VCd, n=195; VCd, n=193), 60 were Asian (D-VCd, n=29; VCd, n=31). Baseline characteristics were well balanced between arms and consistent with the intent-to-treat population. The median age was 66 years, 70% and 58% had heart and kidney involvement, respectively, and 60% had ≥2 organs involved. Cardiac stage I, II and IIIA/B were 28%, 28%, and 43%, respectively. The median duration of treatment was 9.2 mo for D-VCd and 5.3 mo for VCd. Median follow-up was 9.4 mo. The overall hematologic CR rate was 59% for D-VCd and 10% for VCd (odds ratio, 13.2; 95% CI, 3.3-53.7; P<0.0001). D-VCd vs VCd achieved higher rates of very good partial response or better (≥VGPR; 93% vs 61%). MOD-PFS favored D-VCd-treated patients (HR 0.21; 95% CI, 0.06-0.75, P=0.0079). A total of 12 deaths occurred (D-VCd, n=3; VCd, n=9). The most common (≥10%) grade 3/4 TEAEs were lymphopenia (D-VCd 35%/VCd 32%), neutropenia (10%/3%), diarrhea (10%/7%), pneumonia (7%/10%), cardiac failure (7%/10%), hypokalemia (7%/10%), anemia (3%/10%), thrombocytopenia (3%/10%), hypoalbuminemia (3%/10%), and syncope (3%/10%). TEAEs leading to treatment discontinuation occurred in 1 patient in each treatment arm. Conclusion: The addition of DARA SC to VCd was superior to VCd alone in Asian patients, resulting in deeper hematologic responses and improved clinical outcomes, including MOD-PFS, with a safety profile consistent with the overall study population. These data support the use of D-VCd in Asian patients with newly diagnosed AL amyloidosis. Disclosures Suzuki: Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Takeda, Amgen, Janssen and Celgene: Consultancy; Bristol-Myers Squibb, Celgene and Amgen: Research Funding. Wechalekar:Janssen, Takeda, Caelum, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS, Takeda, Amgen, Celgene, Janssen: Consultancy, Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Zhou:Peking University First Hospital: Current Employment. Iida:Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; AbbVie: Research Funding; Merck Sharpe Dohme: Research Funding; Janssen: Honoraria, Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Comenzo:Amgen: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Unum: Consultancy; Caleum: Consultancy; Karyopharm: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. OffLabel Disclosure: To evaluate the efficacy and safety of daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with AL amyloidosis.

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Health-Related Quality of Life in Patients with AL Amyloidosis Treated with Daratumumab, Bortezomib, Cyclophosphamide, and Dexamethasone: Results from the Phase 3 Andromeda Study

Health-Related Quality of Life in Patients with AL Amyloidosis Treated with Daratumumab, Bortezomib, Cyclophosphamide, and Dexamethasone: Results from the Phase 3 Andromeda Study

Efficacy and safety of eltrombopag in aplastic anemia: A multi-center survey in China

目的评估艾曲泊帕联合免疫抑制治疗（IST）在中国再生障碍性贫血（AA）患者中的疗效及安全性。方法调查分析2015年4月至2019年5月来自中国14个血液病治疗中心、连续应用艾曲泊帕治疗至少3个月的输血依赖非重型和重型AA患者临床资料。结果纳入19例IST初治及37例IST难治性AA患者，中位艾曲泊帕治疗时间为7（3~31）个月，中位艾曲泊帕最大稳定使用剂量为75（50~150）mg/d。10例应用艾曲泊帕联合标准IST一线治疗的SAA患者3个月血液学反应（HR）率为60%，完全HR（CR）率为30%；9例艾曲泊帕联合环孢素A（CsA）一线治疗SAA患者后3个月HR率为89%，CR率为44%。19例患者应用艾曲泊帕联合IST一线治疗，至调查随访时HR率为79%，CR率为52.6%。19例CsA±雄激素治疗无效的AA患者，艾曲泊帕开始治疗后3个月HR率为57.9%（11/19），最佳HR率为68.4%；标准IST治疗无效的难治性AA，艾曲泊帕治疗最佳HR率为44%。51%患者应用艾曲泊帕发生不同严重程度的不良反应，以胃肠道不适最为常见。结论艾曲泊帕治疗可加快HR的获得，改善HR质量；残存造血细胞较多的AA患者或可采用非抗胸腺细胞球蛋白免疫抑制联合艾曲泊帕治疗；艾曲泊帕可作为CsA±雄激素治疗无效AA的补救治疗；艾曲泊帕不良反应轻微，多可耐受。

The role of induction therapy before autologous stem cell transplantation in low disease burden AL amyloidosis patients

Background Induction therapy is recommended before autologous stem cell transplantation (ASCT) for AL amyloidosis patients with high disease burden [bone marrow plasma cells (BMPCs) > 10%], but the role of induction therapy before ASCT in patients with low disease burden (BMPCs ≤ 10%) is still unknown. Methods A total of 227 patients with AL amyloidosis were included in this study. Among 227 patients, 124 patients received bortezomib-based induction prior to ASCT and were defined as group A, 35 patients received other chemotherapeutic induction and were defined as group B, and the other 68 patients without induction were defined as group C. We compared the differences of efficacy and prognosis between the three groups. Results The haematological overall response rates (ORR) of groups A, B and C were 91%, 67% and 75%, respectively. The complete response rates (CR) of groups A, B and C were 50%, 25% and 20%, respectively. Both the ORR and CR rates of group A were significantly higher than those of groups B and C. The renal response rates of groups A, B and C were 64%, 46% and 47%, respectively. The cardiac response rates of groups A, B and C were 74%, 45% and 40%, respectively. The renal and cardiac responses rates of group A were also significantly higher than those of the other two groups. After a median follow-up of 44 months, the median OS was not reached. The 5-year estimated overall survival (OS) rates of groups A, B and C were 81%, 57% and 67%, respectively. The median progression-free survival (PFS) was 83 months for all patients. The 5-year estimated PFS rates of groups A, B and C were 61%, 38% and 49%, respectively. Both the OS and PFS of group A were higher than those of both group B and group C. On multivariate analysis, baseline dFLC > 50 mg/L was associated with worse survival, but induction with bortezomib was associated with better survival. Conclusion Our study demonstrated that low disease burden AL patients who are eligible for ASCT may benefit from bortezomib-based induction therapy.

Novel therapeutic choices in immune aplastic anemia.

Aplastic anemia (AA) in its severe form has historically been associated with high mortality. With limited supportive care and no effective strategy to reverse marrow failure, most patients diagnosed with severe AA (SAA) died of pancytopenia complications. Since the 1970s, hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have changed SAA's natural history by improving marrow function and pancytopenia. Standard IST with horse anti-thymocyte globulin plus cyclosporine produces a hematologic response rate of 60 to 70%. In the long term, about one-third of patients relapse, and 10 to 15% can develop cytogenetic abnormalities. Outcomes with either HSCT or IST are similar, and choosing between these modalities relies on age, availability of a histocompatible donor, comorbidities, and patient preference. The introduction of eltrombopag, a thrombopoietin receptor agonist, improved SAA outcomes as both salvage (second-line) and upfront therapy combined with IST. As a single agent, eltrombopag in doses up to 150 mg daily improved cytopenias in 40 to 50% in those who failed initial IST, which associated with higher marrow cellularity, suggesting a pan-stimulatory marrow effect. When eltrombopag was combined with IST as upfront therapy, overall (about 90%) and complete responses (about 50%) were higher than observed extensively with IST alone of 65% and 10%, respectively. Not surprisingly, given the strong correlation between hematologic response rates and survival in SAA, most (>90%) were alive after a median follow-up of 18 months. Longer follow-up and real-word data continue to confirm the activity of this agent in AA. The use of eltrombopag in different combinations and doses are currently being explored. The activity of another thrombopoietin receptor agonist in AA, romiplostim, suggests a class effect. In the coming years, the mechanisms of their activity and the most optimal regimen are likely to be elucidated.

Large Granular Lymphocyte Leukemia and Precapillary Pulmonary Hypertension

Large Granular Lymphocyte Leukemia and Precapillary Pulmonary Hypertension

Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis

AbstractAutologous 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.

MPN-214: Chronic Myeloproliferative Neoplasms in Elderlies: Challenging Issues of Diagnosis and Treatment

Context: Chronic myeloproliferative neoplasms (CMN) in elderlies are the frequently registered clonal stem cell malignancies, being characterized in the advanced phases by recurrent evolution and negative socio-economic sequels. OBJECTIVE: To assert the diagnosis and treatment options in elderlies with CMN. DESIGN: This clinico-analytic study included 78 elderly patients with chronic myeloid leukemia (CML), primary myelofibrosis (PMF) and polycythemia vera (PV), treated at the Institute of Oncology from Moldova between 1995–2020. The diagnosis was proved by histopathological, cytological, molecular examinations and FISH. SETTING: The follow-up and study were completed at the comprehensive cancer center. The study is related to the ambulatory and hospitalized care. PATIENTS: Prefibrotic PMF stage was confirmed in 8 (42.1%) cases, fibrotic stage – in 11 (57.9%). CML was proved in chronic phase in 25 (89.3%) patients, in the accelerated phase in 3 (10.7%). PV was diagnosed in stage IIA in 27 (87.1%) patients, in stage IIB in 4 (12.9%). INTERVENTIONS: TKIs were administered in the newly diagnosed CML patients, in cases of resistance to non-TKIs chemotherapy and interferon-α. PV and PMF patients were treated with busulfan, hydroxycarbamide and interferon-α, combined with phlebotomies in PV. RESULTS: There was no difference of the hematological response (HR) and molecular response rates under TKIs therapy between elderlies and CML totality. In patients ≥60 years 5-year overall survival (OS) was 69% after TKIs therapy, being slightly lower than in CML totality (74%). HR was achieved in all PV patients under chemotherapy and phlebotomies. In relapses, interferon-α provided HR for 61 and 79 months. 10-year OS of elderly PV patients constituted 76.4%, being lower than in PV totality (85.9%). There was no difference of the OS in elderlies under chemotherapy with busulfan and hydroxycarbamide. HR rate and OS were lower under busulfan and hydroxycarbamide treatment in PMF patients, than in PV. CONCLUSIONS: No difference of the OS was revealed in PV elderlies under busulfan and hydroxycarbamide therapy, surpassing the OS in PMF patients. TKIs therapy is a curable option for CML patients regardless the age. The OS in elderlies decays due to more frequent vascular-thrombotic events owing to thrombocytosis.

MM-081: Poems Syndrome: An Update from a Tertiary Care Institute in India from 1993-2020

Abstract: POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes) is a rare entity characterised predominantly by peripheral neuropathy and monoclonal plasmacytosis. Herein, we report a retrospective analysis of 72 patients with diagnosis of POEMS syndrome from 1993-2020 with primary objective of OS and secondary objective of haematological response rates. The median OS of the study cohort was 52.5 months. Eighteen patients had undergone ASCT. Introduction: POEMS is a plasma cell proliferative disorder characterised by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Lambda restriction is the predominant type. Literature provides insights through retrospective analysis of cohorts from across the globe; however, there is paucity of Indian data. Herein, we present retrospective data of 72 cases. Patients and methods: It was a retrospective study. Case files of all patients diagnosed with POEMS syndrome at a tertiary care centre from 1993-2020 were reviewed. The study included POEMS syndrome patients aged >18 years, who had received at least two cycles of therapy, and response evaluation had been done. The primary outcome of the study was overall survival (OS). Study cohort was characterized by descriptive statistics. Results: Seventy-two patients were included in the study. The median age of the study cohort was 45 years (range: 23-70years) with a male to female ratio of 3.8:1. Majority (68/72) of the patients reported peripheral neuropathy during initial presentation. Thirty patients (43%) had ECOG performance status of 4. The mean SPEP recorded was 0.7 gm/dl. There was a paradigm shift in treatment regimen: melphalan/prednisolone was the most commonly used regimen before 2012. However, bortezomib/dexamethasone and lenalidomide/dexamethasone are the commonly used regimens in the recent years. Hematologic response was recorded for 67 patients, of which 38 (56%) had complete response, 16 (23%) had partial response and 12 (17%) had stable disease. The median modified Rankin score improved from a baseline score of 4 to 2 (range: 1-5). Eighteen patients underwent ASCT. Mean melphalan dose used was 140 mg/m2. All 18 patients had a complete haematologic response along with clinical improvement. Conclusion: This retrospective study sheds light about the paradigm shift in management of POEMS syndrome in low-income countries like India. The outcomes have significantly improved with the usage of proteasome inhibitors and immunomodulators along with consolidation with ASCT.

Direct-acting antiviral agents in lymphoproliferative disorders: more complex than expected.

Direct-acting antiviral agents in lymphoproliferative disorders: more complex than expected.

Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management.

AL amyloidosis is characterized by a low-level expansion of an indolent, small plasma cell clone that produces amyloidogenic light chains. Amyloid aggregates or preceding intermediaries cause direct cell damage through their proteotoxicity, and amyloid deposits distort tissue architecture, and, eventually, lead to organ impairment. It is a rare, underdiagnosed disease with a diverse clinical presentation depending on the organ tropism of the amyloid fibrils; cardiac and renal involvement is most common, but any organ can be affected, excluding the central nervous system. A high level of awareness and a systematic approach using newly emerging screening biomarkers is required to achieve early diagnosis. Management should be multidisciplinary as supportive management tailored to management of organ dysfunction is paramount to survival and minimization of treatment-associated toxicity. The initial therapeutic aim is to rapidly eliminate the clonal plasma cell that produces the circulating amyloid precursor and achieve a complete hematologic response, and if possible with undetectable minimal residual disease as assessed by next-generation methods (flow and sequencing), with minimal toxicity. Treatment is tailored to the initial risk assessment of the patients. Treatments are based on regimens adapted from the expanding options that are available for multiple myeloma patients and hematological response rates have improved. Organ response rates are strongly associated with deeper hematologic response but usually lag behind hematological response and are also dependent on the initial organ function reserve. Agents directed against the amyloid deposits have been explored to aid amyloid clearance and improve organ function, but data are still negative.

Efficacy and safety of granulocyte transfusion in children: A single‐center experience

Granulocyte suspension transfusion (GTx) can be used in severely neutropenic patients with infections that cannot be controlled despite appropriate antibiotic therapy. We aimed to evaluate the effectiveness and safety of GTx for the treatment of febrile neutropenia (FEN) in the pediatric age group. Patients who underwent GTx in the Hematology Clinic of Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital between 2013 and 2017 were evaluated retrospectively. Hematologic and clinical response rates, effects on survival, and adverse effects were investigated. Clinical response was defined at two time points: clinical response I was evaluated after each transfusion, while clinical response II was evaluated after the final GTx in a FEN episode. During the study period, 343 GTx were given 107 FEN episodes of 74 patients. The mean number of granulocyte suspensions administered per patient and per FEN episode was 4.6 units and 3.2 units. The mean GTx volume administered was 237 ± 40 mL, and the mean granulocyte count was 2.8 ± 1.3 x 1010 /unit. Hematologic response was attained in 163 (47.6%) of 343 transfusions. Clinical response I was obtained in 88 (25.7%) of the GTx, and clinical response II was attained in 83 (78.5%) of 107 episodes. Life-threatening adverse event was not observed. The cumulative 1-month and 3-month survival rates were 87.8% and 76.5%, respectively. High hematologic response and clinical recovery rates were achieved with GTx, with no limiting adverse effects. Granulocyte transfusion appears to be a safe and effective treatment in pediatric patients with FEN.

Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA

AbstractAlthough no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT03201965.