scholarly journals A Phase 3 Randomized Trial of Inotuzumab Ozogamicin for Newly Diagnosed High-Risk B-ALL: Safety Phase Results from Children's Oncology Group Protocol AALL1732

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3398-3398
Author(s):  
Jennifer L. McNeer ◽  
Maureen M. O'Brien ◽  
Susan R. Rheingold ◽  
Meenakshi Devidas ◽  
Zhiguo Chen ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Bacterial Infections ◽  
Sinusoidal Obstruction Syndrome ◽  
Hepatic Toxicity ◽  
Oncology Group ◽  
Inotuzumab Ozogamicin ◽  
Phase 3 ◽  
Hematopoietic Stem ◽  
Grade 3

Abstract Background: The CD22-directed antibody-drug conjugate inotuzumab ozogamicin (InO) is FDA-approved for adults with relapsed/refractory (R/R) CD22+ B-ALL and highly active in children with multiply R/R CD22+ B-ALL. Notable toxicities include cytopenias and hepatic toxicity, including sinusoidal obstruction syndrome (SOS) occurring primarily after subsequent hematopoietic stem cell transplantation (HSCT). The incorporation of InO into frontline ALL therapy for patients (pts) with CD22+ high-risk B-ALL who are not anticipated to require HSCT in first remission may optimize use of this effective agent without incurring significant SOS risk by minimizing relapse and therefore potential need for future HSCT. Methods: Children's Oncology Group (COG) AALL1732 is a phase 3 trial for pts 1-24 years of age with B-ALL who have high-risk features based on age, white blood cell count, or presence of extramedullary disease at diagnosis (Figure 1). Pts receive a 4-drug induction followed by augmented BFM consolidation. Those with surface CD22 expression on >20% of blasts at diagnosis and bone marrow minimal residual disease <0.01% by flow cytometry by the end of consolidation are eligible for randomization to chemotherapy alone (Arm A) or chemotherapy plus 2 cycles of InO (Arm B) delivered between consolidation and interim maintenance 1 (IM1), and between IM1 and Delayed Intensification (DI). A planned safety phase was conducted to assess hepatic toxicity, chemotherapy delays, and infectious toxicity in the first 50 randomized pts followed through the completion of DI. Results: Forty-eight pts continued on therapy after randomization, (Arm A: 25, Arm B: 23), with median age 12 years and body surface area 1.4m 2 on each arm (Table 1). There were no statistically significant differences in grade ≥3 ALT or bilirubin levels between Arms A and B through day 1 of DI. During DI, 4 pts on Arm B had grade 3 hyperbilirubinemia compared to none on Arm A, all in the setting of concurrent infection. The rates of SOS did not cross protocol-defined safety thresholds and were not statistically different between arms; on Arm A, 1/25 pts (4%, 1 grade 3 event) and on Arm B, 3/23 pts developed SOS (13%, 1 grade 4, 2 grade 2). The patient with grade 4 SOS discontinued protocol therapy. The duration of the IM1 block of therapy was significantly longer for patients on Arm B compared to those on Arm A (mean duration of 90 days (sd 15.3) versus 75.5 days (sd 14.4), p=0.002). Day 1 HD-MTX clearance to <0.1mM exceeded 96 hours in 6/22 (27%) pts on Arm B, compared to 1/25 (4%) on Arm A (p=0.04). There was a >14-day delay in the start of the second (Day 15) HD-MTX in 4/23 pts (17.4%) on Arm B compared to 0/25 on Arm A, p=0.046. In contrast, time to MTX clearance and rate of >96-hour clearance were not significantly different between the arms for the other HD-MTX doses (Days 15, 29, 43). Omission of oral 6MP occurred at a significantly higher frequency on Arm B compared to Arm A at several time points in IM1, with an association between HD-MTX clearance of >96 hours and the need to hold oral 6MP (p=0.011, p=0.018, and p=0.042 for days 1, 15, and 43, respectively). During DI, sepsis occurred more frequently in pts on Arm B. There were 6 (27%) Grade 3 events and 6 (27%) ≥Grade 4 events among 22 Arm B patients, including 3 pts with multiorgan failure and one death. In contrast, among 25 pts on Arm A, there were 2 (8%) Grade 3 sepsis events and no ≥Grade 4 events. The rate of sepsis was significantly higher on Arm B (12 of 22, 54%) compared to Arm A (2 of 25, 8%, p= 0.001). The majority of sepsis events were due to bacterial infections, and 8 of 12 events on Arm B occurred in the second half of DI. Conclusion: Planned safety phase analysis of the first 50 randomized pts demonstrated increased rates of delayed MTX clearance following the first HD-MTX infusion in IM1 and more sepsis events due to bacterial infections during DI in Arm B patients. Hepatic toxicity and SOS occurred infrequently and did not differ significantly between arms. We plan to amend AALL1732 to decrease the dose of InO by 20% and increase hydration for the first HD-MTX infusion. We will recommend prophylaxis with broad-spectrum antibiotics during periods of neutropenia in DI as well as monitoring of serum IgG levels, with replacement for IgG <400 mg/dL. A second safety phase will evaluate the effectiveness of these modifications in the next 50 randomized pts. Figure 1 Figure 1. Disclosures McNeer: Jazz Pharmaceuticals: Other: Advisory Board Member. O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Wood: Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement; Pfizer, Amgen, Seattle Genetics: Honoraria. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees.

Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1625-1625
Author(s):  
Keita Kirito ◽  
Norio Komatsu ◽  
Kazuya Shimoda ◽  
Hikaru Okada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Spleen Size ◽  
Phase 2 ◽  
Spleen Volume ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Starting Dose ◽  
Grade 3 ◽  
Eortc Qlq

Abstract BACKGROUND: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly and MF-related symptoms, and has been associated with improved overall survival in patients (pts) with MF in randomized clinical trials. Results from the phase 2 Asian multinational study (NCT01392443) supported these findings in Asian pts, including 30 Japanese pts. The current study was initiated to collect further data on the safety and efficacy of ruxolitinib in pts with MF and included intermediate (Int)-1-risk pts and those with a platelet (PLT) count of 50 to < 100 × 109/L, 2 pt populations not included in the phase 3 COMFORT studies or the phase 2 Asian study. METHODS: Pts with primary MF (PMF), post-polycythemia vera (PPV) MF, or post-essential thrombocythemia (PET) MF classified as high-risk, Int-2 risk, or Int-1 risk with a palpable spleen (≥ 5 cm from costal margin) were included. The primary objective was to assess safety of ruxolitinib. Efficacy endpoints included changes in spleen size and patient-reported outcomes (EORTC QLQ-C30 symptoms and functional scales and the 7-day modified MFSAF v2.0). All pts were to receive ruxolitinib for 24 wk with the starting dose based on PLT count at baseline (50 to ˂ 100 × 109/L, 5 mg twice daily [bid]; 100 to 200 × 109/L, 15 mg bid; ˃ 200 × 109/L, 20 mg bid) and adjusted for each pt to maximize safety and efficacy (minimum, 5 mg bid; maximum, 25 mg bid). The primary analysis occurred when all pts completed 24 wk or discontinued. RESULTS: Overall, 51 pts (PMF, n = 23; PPV-MF, n = 14; PET-MF, n = 14) were treated. Most pts were Int-2 (33.3%) or high risk (54.9%); 11.8% were classified as Int-1. The median age was 65 years (range, 44-85 years), and 52.9% (n = 27) were male. The median palpable spleen length was 16.5 cm (range, 2-30 cm), and the median spleen volume was 2028.7 cm3 (range, 480-4682 cm3). Median hemoglobin at baseline was 99.0 g/L (range, 62-141 g/L), and median PLT count was 247 × 109/L (range, 57-1265 × 109/L); 13.7% of pts had a baseline PLT count of 50 to < 100 × 109/L. Most pts received a starting dose of 20 mg bid (62.7%; n = 32) or 15 mg bid (23.5%; n = 12); the rest started treatment at 5 mg bid. Most pts completed treatment as per protocol (86.3%; n = 44); 9.8% (n = 5) discontinued due to adverse events (AEs). Other reasons for discontinuation included disease progression and loss to follow-up (2.0% each). The most common hematologic AEs were anemia (62.7%; grade 3/4, 47.1%) and thrombocytopenia (29.4%; grade 3/4, 7.8%). Nonhematologic AEs in ≥ 10% of pts included constipation (13.7%; grade 3/4, 0%), abnormal hepatic function (11.8%; grade 3/4, 3.9%), and nasopharyngitis (11.8%; grade 3/4, 0%). No deaths occurred on study. At wk 24, 30.0% of evaluable pts (15/50) experienced ≥ 50% reduction in palpable spleen length from baseline; 26.0% (13/50) had a ≥ 35% reduction in spleen volume. The majority of pts (52.0%; 26/50) had a ≥ 50% reduction in palpable spleen length from baseline at any time by wk 24; 38.0% (19/50) had a ≥ 35% reduction in spleen volume by wk 24. Ruxolitinib treatment led to clinically significant improvements in symptoms, with 75.0% of evaluable pts (30/40) achieving a ≥ 50% reduction from baseline in MFSAF total symptom score at wk 24. Improvements were also observed in quality of life and role functioning (as assessed by the EORTC-QLQ), with pts reporting reductions in MF-related symptoms, including fatigue, pain, and appetite loss. Overall, IgM, CD3, CD4, and CD8 levels remained stable during treatment; IgG levels decreased slightly in the first 4 wk but then increased to near baseline levels (Figure). CONCLUSIONS: As observed in other studies of ruxolitinib, most pts in this study experienced spleen size reductions and improvement in symptoms. The most common AEs were anemia and thrombocytopenia, consistent with previous reports. Additionally, this study evaluated the effect of ruxolitinib on the levels of different immune markers, an analysis not conducted in previous studies with ruxolitinib, and identified no negative effects on the levels of these markers during the course of treatment. The safety and efficacy of ruxolitinib here is consistent with the phase 3 COMFORT studies and the phase 2 Asian study. These findings indicate that ruxolitinib is a safe and effective therapy in Japanese pts with MF, including Int-1-risk pts and those with PLT counts 50 to < 100 × 109/L. Disclosures Kirito: Novartis Pharma KK: Honoraria. Shimoda:Novartis: Consultancy, Honoraria. Okada:Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Yonezu:Novartis Pharma K.K.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Safety and Efficacy of Ruxolitinib in an 1869-Patient Cohort of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2799-2799 ◽  
Author(s):  
Renato Tavares ◽  
Giuseppe A. Palumbo ◽  
Philipp Le Coutre ◽  
Francesca Palandri ◽  
Haifa Kathrin Al-Ali ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Costal Margin ◽  
Phase 3 ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Expanded Access ◽  
Grade 3

Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that demonstrated improvements in splenomegaly and disease-related symptoms, as well as improved survival, in patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF), and has proved superior to placebo and best available therapy in the phase 3 COMFORT studies. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of RUX in pts with MF and includes patients with no access to RUX outside a clinical trial. As of Dec 2014, final enrollment was 2233 pts in 26 countries. METHODS: Eligible pts had Int-2- or high-risk MF with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm from the costal margin). Pts received starting doses of RUX based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to < 100 × 109/L], 15 mg bid [100 to 200 × 109/L], or 20 mg bid [> 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of RUX. Additional analyses included changes in palpable spleen length and symptom scores as measured by the FACT-Lymphoma total score (FACT-Lym TS). The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study. RESULTS: This analysis includes 1869 pts (primary MF, 59.1%; n = 1105) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2015). At baseline, median age was 67 y (range, 18-89 y); 54.1% were male; median palpable spleen length was 12 cm below the costal margin; 87 pts did not have splenomegaly. Median hemoglobin (Hb) was 106 g/L, and 38.9% of pts had Hb levels ˂ 100 g/L; median platelet count was 257 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.7 and 33.2, respectively. At data cutoff, 37.0% of pts remained on treatment; 26.1% had completed treatment per protocol. Primary reasons for discontinuation included adverse events (AEs; 17.4%), disease progression (8.2%), and death (3.4%). Median exposure was 13.6 months; the median average daily dose was 36.7 mg for pts starting at 20 mg bid (n = 1168; 62.5%) and 23.2 mg for pts starting at 15 mg bid (n = 559; 29.9%). The majority of pts (66.0%) had dose modifications, and 26.2% had a dose interruption. Grade 3/4 hematologic AEs included anemia (34.0%), thrombocytopenia (14.9%), and neutropenia (3.9%), which led to discontinuation in 2.2%, 3.3%, and 0.2% of pts, respectively. The most common nonhematologic AEs (≥ 10%) were pyrexia (14.5%), asthenia (13.8%), diarrhea (12.4%), and fatigue (10.3%), and were primarily grade 1/2; grade 3/4 AEs were low overall (≤ 2%), except pneumonia (3.9%), which led to discontinuation in 9 pts (0.5%). Rates of infections were low; all-grade infections ≥ 5% included pneumonia (6.2%), urinary tract infection (5.7%), and nasopharyngitis (5.3%). Tuberculosis was reported in 5 pts (0.3%; grade 3/4, 0.1%); hepatitis B was reported in 1 pt (0.1%; grade 3/4, 0.1%). At wk 24 and 48, 57.2% (742/1297) and 62.0% (588/949) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 22.9% (297/1297) and 19.0% (180/949) had 25% to 50% reductions, respectively. Most pts (70.5%; 1208/1713) experienced a ≥ 50% reduction at any time; 23.3% (399/1713) had complete resolution of splenomegaly (Figure). At wk 24 and 48, 96.6% (57/59) and 91.5% (43/47) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen; 1.7% (1/59) and 4.3% (2/47) had a spleen that was 0-5 cm, and 1.7% (1/59) and 4.3% (2/47) had a spleen ≥ 5 cm. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (43.0% [525/1220]; 47.1% [593/1258]) and wk 48 (43.2% [368/852]; 45.7% [396/867]). Similar responses were seen in pts without a palpable spleen (FACT-Lym TS: wk 24, 44.0% [22/50]; wk 48, 36.1% [13/36]; FACIT-Fatigue: wk 24, 49.1% [27/55]; wk 48, 35.1% [13/37]). CONCLUSIONS: To date, JUMP includes the largest cohort of pts with MF treated with RUX. Consistent with previous findings, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. As observed previously, most pts experienced reductions in splenomegaly and symptoms with RUX treatment. Clinically meaningful improvements in symptoms were also seen in pts with no palpable spleen, a pt group not included in the COMFORT studies. Overall, the safety and efficacy profile of RUX in JUMP is consistent with that in the phase 3 COMFORT studies. Disclosures Palumbo: Novartis: Honoraria, Other: Advisory Board. Le Coutre:Novartis: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ullrich:Novartis: Honoraria. Brittain:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foltz:Promedior: Research Funding; Gilead: Research Funding; Novartis: Honoraria, Research Funding. Raanani:Bristol-Myers Squibb: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board. Gupta:Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghosh:Novartis Pharmaceuticals Corporation: Employment. Tannir:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Vannucchi:Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621

2022 ◽  
Author(s):  
Maureen M. O'Brien ◽  
Lingyun Ji ◽  
Nirali N. Shah ◽  
Susan R. Rheingold ◽  
Deepa Bhojwani ◽  
...  
Keyword(s):  
Phase Ii Trial ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Oncology Group ◽  
Inotuzumab Ozogamicin ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Grade 3 ◽  
Minimal Residual ◽  
Count Recovery

PURPOSE Children's Oncology Group trial AALL1621 was conducted to prospectively determine the safety and efficacy of inotuzumab ozogamicin (InO) in pediatric and adolescent patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS This single-arm phase II trial enrolled patients age 1-21 years with R/R CD22-positive B-ALL. In cycle 1, InO dosing was 0.8 mg/m2 intravenously on day 1 and 0.5 mg/m2 on days 8 and 15 of a 28-day cycle with response evaluation at day 28. Using a two-stage design, the trial was continuously monitored for dose-limiting toxicities and sinusoidal obstruction syndrome (SOS). CD22 expression was retrospectively evaluated by central flow cytometry. RESULTS Forty-eight patients were evaluable for response and toxicity; 19 had complete response (CR) and nine CR with incomplete count recovery (CRi) after cycle 1 (CR/CRi rate: 58.3%; two-sided 90% CI, 46.5 to 69.3). Twenty-seven of 28 patients with CR or CRi had minimal residual disease measured by flow cytometry; 18 (66.7%) had minimal residual disease < 0.01%. Seven of 28 patients (25%) with CR or CRi had delayed count recovery past day 42 in cycle 1. Three (6.3%) patients had grade 3 ALT elevation and one patient had grade 3 hyperbilirubinemia in cycle 1. Of 21 patients undergoing hematopoietic stem-cell transplantation after InO, 6 (28.6%) developed grade 3 SOS. Partial CD22 expression and lower CD22 site density were associated with lower likelihood of response to InO. CONCLUSION InO is effective and well tolerated in heavily pretreated children and adolescents with R/R CD22-positive B-ALL. SOS after hematopoietic stem-cell transplantation and prolonged cytopenias were notable. CD22 modulation was identified as a mechanism of resistance. Expanded study of InO combined with chemotherapy is underway.

scholarly journals Inotuzumab Ozogamicin Compassionate Use for French Pediatric Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5203-5203 ◽  
Author(s):  
Charlotte Calvo ◽  
Benoit Brethon ◽  
Aurelie Cabannes-Hamy ◽  
Dalila Adjaoud ◽  
Benedicte Bruno ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Body Surface ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Sinusoidal Obstruction Syndrome ◽  
Compassionate Use ◽  
Inotuzumab Ozogamicin ◽  
Hematopoietic Stem ◽  
Grade 3

Abstract Introduction: Inotuzumab ozogamicin (INO) is an anti-CD22-drug conjugate therapeutic agent, in which a cytotoxic agent, calicheamicin, is conjugated to a humanized IgG4 anti-CD22 mAb (de Vries et al., Leukemia, 2012). As CD22 expression is confined to the B-cell lineage and is largely expressed in mature and immature B-cell malignancies, INO represents an attractive drug to treat B-cell acute lymphoid leukemia (ALL). INO has been evaluated in clinical trials and its efficacy has been reported in adult and elderly patients (pts) with ALL (Kantarjian et al., NEJM, 2016; Lancet Oncol 2018 and Cancer 2018). Since half of the total number of cases of ALL occurs in children and teenagers and it is the most frequently diagnosed malignancy in children, with the vast majority arising from B-cell lineage (85%), INO is also a drug of interest for the 15% of pediatric pts who are not cured by current treatments. We here report French pediatric pts with refractory or relapsed (r/r) B-cell ALL who were treated by INO through a compassionate use access program. Methods: French pediatric hematology centers provided retrospective clinical follow-up on pts' ≤ 18 years old affected by r/r B-cell ALL who received at least one dose of INO, provided by Pfizer through a compassionate use program following authorization by the French regulatory agency (ANSM) between 2015 and 2017. All pts were treated according to the adult phase 3 clinical trial dose of 1.8 mg/m2 during the first course divided as followed: 0.8 mg/m2 of body surface at day 1 and 0.5 mg/m2 at day 8 and 15. A second course could be repeated at the same dosage if the response was not complete after the first course. Then the consolidation courses of treatment could be continued at the dose of 1.5 mg/m2 divided as 0.5 mg/m2 of body surface at day 1, 8 and 15, up to 3 total cycles. Results: Eleven pts aged from 3 to 18 years old received INO; and were: 2 between 1 and 10 years old, 4 between 10 and 15 and 5 between 15 and 18. They received from 1 to 3 cycles of INO. They were heavily pretreated, as 6 of them received INO while refractory to the treatment of a first relapse, and 5 of them in treatment of second relapse or more. Prior to INO therapy, 4/11 pts had undergone allogenic hematopoietic stem cell transplantation (HSCT) and 7/11 pts had received anti-CD19 therapy with either Blinatumomab (6/7) or CAR-T cells (1/7). Pre-INO treatment medullary status was M3 (>25% blasts) for 8/11 pts, M2 (5-25%) for 2 pts and M1 (<5%) with positive minimal residual disease (MRD) and extra-medullary disease for 1 patient (pt). Eight pts were in complete remission (CR) after one cycle (M2/M3 marrow prior to INO: 7, M1: 1), including 2 pts with an undetectable MRD (< 10-5). These 2 pts received a second cycle of INO and were brought to HSCT; both of them are alive (20 months (m)+, 27 m+). The 6 remaining pts in CR but MRD+ subsequently died: 1) 5 received a second cycle of INO without documentation of MRD negativity. All of them relapsed whatever the following treatment (time to disease progression ranged from 1 week to 17 months). 2) 1 pt was brought to HSCT but died of cardiac failure 3 months after the procedure. As observed in adults, hepatic and hematologic adverse events were observed. All pts developed hematologic toxicities, 10/11 pts with grade 3/4 anemia, neutropenia or thrombocytopenia. Febrile neutropenia of grade 3/4 occurred for 5 pts. Cholestasis with grade 3/4 elevations of GGT or transaminases was noted in 4/11 pts. Sinusoidal obstruction syndrome (SOS) occurred in 1 pt who had previously undergone HSCT, during his first course of INO. Two pts who subsequently underwent HSCT developed SOS during transplant. All of these 3 pts recovered normal hepatic function. None of them died from INO direct toxicities. Conclusion: Toxicities developed by these young patients were very similar to the ones reported in adults with hepatic and infectious toxicities. The incidence of SOS seems significant in patients that underwent HSCT either before or after INO treatment. INO showed promising results in pediatric compassionate use program in our French cohort, similarly to the one reported by Bhojwani D et al. (ASCO abstract, 2017). Its safety and efficacy in r/r B-cell ALL are to be further investigated in pediatric populations within prospective clinical trials currently underway in EU and US. Disclosures Baruchel: Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Celgene: Consultancy; Servier: Consultancy; Shire: Research Funding.

Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10512-10512 ◽  
Author(s):  
Deepa Bhojwani ◽  
Richard Sposto ◽  
Nirali Shah ◽  
Vilmarie Rodriguez ◽  
Maureen Megan O'Brien ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Sinusoidal Obstruction Syndrome ◽  
Cell Transplant ◽  
Inotuzumab Ozogamicin ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Heavily Pretreated ◽  
Grade 3

10512 Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1st-5threlapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( > 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.

scholarly journals Clinical Outcomes Following Treatment with Gilteritinib or Quizartinib in Patients with Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Alexander E. Perl ◽  
Qiaoyang Lu ◽  
Alan Fan ◽  
Nahla Hasabou ◽  
Erhan Berrak ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 3 ◽  
Hematopoietic Stem ◽  
Travel Costs ◽  
Baseline Characteristics ◽  
Acute Myeloid

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4304-4304
Author(s):  
Caspar Da Cunha-Bang ◽  
Rudy Agius ◽  
Arnon P. Kater ◽  
Mark-David Levin ◽  
Anders Österborg ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Severe Infection ◽  
Newly Diagnosed ◽  
Risk Of Infection ◽  
Advisory Committees ◽  
Educational Grant ◽  
Travel Grant ◽  
Grade 3

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (>65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

Phase I Study of Bortezomib(Bz), Pegylated Doxorubicin(DOX) and Dexamethasone(dex); ( VDD) with Escalating Doses of Cyclophosphamide(Cy) in Patients with Newly Diagnosed Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 617-617
Author(s):  
Melissa Alsina ◽  
Rachid Baz ◽  
Jose L Ochoa ◽  
Jyotishankar Raychaudhuri ◽  
Kara Kosakowski ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Stem Cell Mobilization ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Long Term Outcome ◽  
Cell Mobilization ◽  
Grade 3

Abstract Abstract 617 Background: The VDD treatment regimen has been shown to be highly effective as initial therapy for multiple myeloma. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We report the results from a Phase I trial combining VDD with escalating doses of cyclophosphamide ( CVDD) in patients (Pts) with newly diagnosed myeloma. Methods: Pts received Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 and Cy 250-750 mg/m2 on day 1, for up to eight 21-day cycles, at four planned dose levels (Cy/Bz: 250/1.0, 500/1.0, 750/1.0, 750/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs) grade 3 non-hematologic toxicity; thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; Grade 4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Pts with Grade 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Pts with at least partial response ( PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after 6 cycles. Responsive pts with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t (4;14), t(14;16) or deletion of 17 p by FISH, completed 8 cycles of therapy. Results: 26 pts have been enrolled to date: 12 in phase l, and 14 additional pts at the maximum planned dose (MPD). Median age 60 yrs, 62% men, 50% IgG MM, 81% with ISS stage II/III. Pts have received a median of 6 cycles; 17 have completed all 6-8 cycles, 1 has discontinued therapy. No DLTs were observed in the phase I portion of study. Dose reductions in cycle 2 and beyond have occurred in 31% of patients. Toxicities to date have been manageable, including all Grade 3/4 hematological toxicities (4-35%), Grade 3 hand foot syndrome( 15%), Grade 3 pneumonia (8%), Grade 3 UTI (8%), and Grade 3/4 metabolic (19%). There were no grade 3/4 PNY. There was 1 treatment-related mortality secondary to infection. The overall response rate in patients that have completed at least 4 cycles of therapy (ORR; ≥PR) is 90%, including 57% ≥VGPR, and 24% CR. ORR and VGPR rates were similar in patients with standard or high risk cytogenetics. Nine patients have proceeded to transplant and all have had successful stem cell mobilization with G-CSF alone. Conclusions: CVDD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at CY 750 mg/m2, Bz 1.3 mg/m2, DOX 30 mg/m2, and Dex 20 mg, with phase II enrollment ongoing. Stem cell mobilization has been successful in all pts, with transplant course in pts otherwise unremarkable. Updated efficacy will be presented at the meeting. Disclosures: Alsina: Millenium: Research Funding, Speakers Bureau; Ortho Biotech: Research Funding, Speakers Bureau.

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

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