Prolonged Hematologic Toxicity Research Articles

Comprehensive characterization of cytopenia after chimeric antigen receptor-T cell infusion in patients with relapsed or refractory multiple myeloma

BackgroundMany studies have demonstrated the effectiveness of chimeric antigen receptor-T (CAR-T) cell therapy for relapsed or refractory multiple myeloma (RRMM), but the hematologic toxicity has not been well characterized. MethodsA total of 111 adults with RRMM who received BCMA CAR-T cells, BCMA + CD19 CAR-T cells or tandem BCMA/CD19 dual-target (BC19) CAR-T cells infusion were enrolled. We characterized cytopenia and hematologic recovery at different time points after CAR-T-cell therapy, analyzed the effect of cytopenia on prognosis and identified the risk factors. ResultsPatients had a high probability of cytopenia, with anemia, neutropenia and thrombocytopenia occurring in 92%, 95% and 73%, respectively. There were 60 (54%) patients had prolonged hematologic toxicity (PHT) after D28. The median hemoglobin and platelet count were significantly lower at D28 post-CAR-T cell therapy than at baseline. Hemoglobin increased to above baseline at D90. The median absolute neutrophil count was lower than baseline at D0 and D28, and it recovered to baseline at D180. The baseline level of lactate dehydrogenase was associated with thrombocytopenia. Extramedullary involvement was associated with hemoglobin recovery, while the baseline level of albumin and types of CAR-T were related to platelet recovery. Patients with anemia at baseline and at D0, D180 and D360 had shorter progression-free survival (PFS), while anemia at D0, D60, D180 and D360 was associated with shorter overall survival (OS). Neutropenia at D0 was associated with shorter PFS and patients with neutropenia at D90 or D180 had shorter OS. Patients with thrombocytopenia at any time had shorter PFS and OS. Compared to patients without PHT, patients with PHT had shorter PFS and OS. ConclusionsThe majority of RRMM patients treated with CAR-T cells experienced cytopenia. Cytopenia occurred at specific time points was associated with a poorer prognosis.

Impact of late immune effector cell associated hematotoxicity (ICAHT) and prolonged neutropenia after CAR-T therapy on infection and survival outcomes.

7041 Background: Prolonged hematologic toxicity is a common side effect of chimeric antigen receptor T-cell (CART) therapy. The EHA/EBMT panel developed the late ICAHT grading which incorporates depth of neutropenia after Day 30. Recently, the early ICAHT grade (D 0-30) was associated with infection (infx) and survival outcomes. Here, we evaluate the impact of late ICAHT and neutropenia on survival and infx outcomes after CD19 CART. Methods: We included two cohorts of adult patients (pts) with large B cell lymphoma (LBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL) who received commercial CD19 CART. Late was graded based on depth of neutropenia after D30 (G1 ≤ 1.5; G2 ≤ 1.0; G3 ≤ 0.5; G4 ≤ 0.1 G/L) and pts were censored for relapse, progression, or loss of follow up. Infxs after D30 were graded per CTCAE as mild G ≤ 2 or severe G ≥ 3. Cohort 1 included pts from 8 US medical centers for survival outcomes. Only data for severe infx was collected from D30-D100 and longer term infx data was not available. Landmark survival analysis at D+100 was performed using the Kaplan-Meier method and multivariate cox proportional hazards. To assess long term late infx outcomes, cohort 2 included pts at Vanderbilt with granular cytopenia and infx data (D30-365). Results: Cohort 1 included 277 pts with LBCL of whom 143 received axi-cel, 61 tisa-cel, and 72 liso-cel with median follow up 395 days (range 30-1763). By D100, there were 111 (40%) without, 89 (41%) with mild to moderate (G1-G2), and 53 (19%) with severe (G3-G4) late ICAHT. There were 13 pts (6%) with severe infx which was not associated with severe ICAHT (p=0.68). In multivariate landmark survival analysis using previously published covariates, severe late ICAHT was not associated with PFS (HR 1.64, p=0.11) or OS (HR 1.54, p=0.17); however, D100 neutropenia (ANC ≤ 1000) was associated with inferior PFS (HR 2.00, p=0.002) and OS (HR 1.95, p=0.003). NRM was 11% and associated with D100 neutropenia (p=0.015) but not late ICAHT (p=0.15). Cohort 2 had 43 pts (35 LBCL, 7 MCL, 1 FL) with median follow up 483 days (range 233-2133). 34 pts received axi-cel, 2 tisa-cel, and 7 brexu-cel. By 1 yr, there were 10 (23%) without, 27 (63%) with mild to moderate, and 6 (14%) with severe late ICAHT. There were 52 infxs by 1 yr and 16 pts (37%) had no infx. Median time to first infx after D30 was 165 days (range 31-365). There were 31 (60%) mild and 21 (40%) severe infx. IVIG was used in 28 (65%) and G-CSF in 27 (62%). Only 1 pt with severe ICAHT had severe infx. Late ICAHT and neutropenia were not associated with severe infection in logistic regression. Conclusions: These data did not show an association between EHA/EBMT late ICAHT grading and infx after D30 or survival. A detailed reporting of T and B cell reconstitution data may provide clues to better predict late infx. Persistent neutropenia at D100 was associated with inferior PFS and OS which needs validation in future studies.

Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients

BackgroundChimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM), leading to unprecedented responses in this patient population. Idecabtagene vicleucel (ide-cel) has been recently approved for treatment of triple-class exposed RRMM. We report real-life experiences with the commercial use of ide-cel in RRMM patients.MethodsWe performed a retrospective analysis of the first 16 triple-class exposed RRMM patients treated with ide-cel at a single academic center. We assessed toxicities, response to treatment, CAR T expansion and soluble BCMA (sBCMA) levels.ResultsWe identified 16 consecutive RRMM patients treated with ide-cel between 06–10/2022. Median age was 69 years, 6 (38%) patients had high-risk cytogenetics, 3 (19%) R-ISS stage III, and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3–12). Manufacturing success rate was 88% (6% required second lymphapheresis, 6% received an out-of-specification product). At 3 months, the overall response rate (ORR) was 69% (44% sCR, 6% CR, 19% VGPR). Cytokine release syndrome (CRS) occurred in 15 (94%) patients (88% G1, 6% G2), immune effector-cell associated neurotoxicity syndrome (ICANS) in 1 (6% G1), febrile neutropenia in 11 (69%), and infections in 5 (31%). Prolonged hematologic toxicity occurred in 4/16 (25%) patients. Other non-hematological toxicities were elevated hepatic enzymes (38%), colitis (6%, G3) and DIC (6%, G2). Responses were more frequent in patients with higher CAR T expansion (100% vs 38%), and lack of decrease or plateau of sBCMA levels was typically observed in non-responders.ConclusionsWe report one of the first cohorts of RRMM treated with commercial ide-cel. The ORR was 69% and safety profile was manageable, but prolonged hematologic toxicity still represents a major challenge. Responses correlated with in vivo CAR T cell expansion, underlining the need of further research to optimize CAR T expansion.

Low-dose administration of prednisone has a good effect on the treatment of prolonged hematologic toxicity post-CD19 CAR-T cell therapy.

Hematologic toxicity (HT) is a joint adverse event after CAR-T cells infusion. Some patients experience prolonged hematologic toxicity (PHT), which is challenging to treat. We collected clinical data from patients with relapsed refractory B-ALL treated with CD19 CAR-T cells. Patients with PHT who did not respond to erythropoietin, platelet receptor agonists, transfusion, or G-CSF and eventually received low-dose prednisone therapy were included in the analysis. We retrospectively analyzed the efficacy and safety of low-dose prednisone on PHT. Among 109 patients treated with CD19 CAR-T cells, 78.9% (86/109) of patients were evaluated as PHT. Of these, 15 patients had persistent hematological toxicity after infusion (12 were grade 3/4 cytopenia, 12 were trilineage cytopenia and 3 were bilineage cytopenia), 2 developed cytopenia without apparent cause after D28. The initial prednisone dose was 0.5 mg/kg/day, and the median response time was 21 days (7-40 days). The recovery rate of blood count was 100%, and the complete recovery rate ranged from 60% to 66.67%. Especially exciting was that HT recurred in 6 patients after stopping prednisone. They were relieved again after the administration of prednisone. The median follow-up time was 14.97 months (4.1-31.2 months). Twelve-month duration of PFS and OS rates were 58.8% (±11.9%) and 64.7% (±11.6%). We did not observe any other side effects of prednisone apart from drug-controllable hyperglycemia and hypertension. We suggest that low-dose prednisone is a beneficial and tolerable therapy for PHT after CAR-T cells. The trials have been registered at www.chictr.org.cn as ChiCTR-ONN-16009862 (November 14, 2016) and ChiCTR1800015164 (March 11, 2018).

Cytokine profiles are associated with prolonged hematologic toxicities after B-cell maturation antigen targeted chimeric antigen receptor–T-cell therapy

Background aimsThe considerable efficacy of B-cell maturation antigen–targeted chimeric antigen receptor (CAR)–T-cell therapy has been extensively demonstrated in the treatment of relapsed or refractory multiple myeloma. Nevertheless, in clinical practice, prolonged hematologic toxicity (PHT) extends hospital stay and impairs long-term survival. MethodsThis retrospective study reviewed 99 patients with relapsed or refractory multiple myeloma who underwent B-cell maturation antigen CAR–T-cell therapy at our institution between April 2018 and September 2021 (ChiCTR1800017404). ResultsAmong 93 evaluable patients, the incidence of prolonged hematologic toxicities was high after CAR–T-cell infusion, including 38.71% (36/93) of patients with prolonged neutropenia, 22.58% (21/93) with prolonged anemia and 59.14% (55/93) with prolonged thrombocytopenia. In addition, 9.68% (9/93) of patients experienced prolonged pancytopenia. Our multivariate analyses identified that cytokine profiles were independent risk factors for PHTs, whereas a sufficient baseline hematopoietic function and high CD4/CD8 ratio of CAR-T cells were protective factors for PHTs after CAR–T-cell infusion. Subgroup analyses found that the kinetics of post-CAR-T hematologic parameters were primarily determined by the collective effects of cytokine release syndrome and baseline hematopoietic functions, and showed influential weights for the three lineages. ConclusionsOur findings improve the understanding of the impact of cytokines on hematopoietic functions, which could contribute to the mechanism investigation and exploration of potential intervention strategies.

Incidence, Risk Factors and Outcomes of Pancytopenia Following Chimeric Antigen Receptor (CAR)-T Cell Therapy in Relapsed Refractory Diffuse Large B Cell Lymphoma

Introduction: CD19 directed CAR-T cell therapy has changed treatment paradigm of relapse refractory diffuse large B cell lymphoma (DLBCL). It is associated with certain unique toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), B-cell aplasia and hypogammaglobulinemia. However, the information on hematologic toxicity including neutropenia, thrombocytopenia and anemia is limited.Methods: We retrospectively evaluated patients who received CAR-T cell therapy for relapsed refractory DLBCL to estimate incidence, risk factors and outcomes of hematological toxicity especially pancytopenia. We also evaluated the impact of prophylactic G-CSF administration on incidence and duration of neutropenia, and infectious complications.Results: Between April 2018 and December 2020, 30 adult patients received CAR-T cell therapy (AxiCel=22, TisaCel=8). Median age of the population was 57 years (range, 23-81). Median time from diagnosis to CAR-T cell therapy was 674 days. Four patients each had double expressor and double hit subtypes. Seventy percent patients had extra-nodal disease, 60% of patients received three or more lines of therapy, 27% of patients received prior autologous stem cell transplant (autoSCT), and 23% patients received bridging therapy. All patients received Fludarabine and Cyclophosphamide (Flu/Cy) as a lymphodepleting therapy. CRS and ICANS were noted in 83% and 37% patients, respectively. One-year progression-free and overall survival were 49.76% and 85.91%, respectively.After CAR-T cell therapy, 93% (28/30) patients developed neutropenia with 17 (57%) experiencing absolute neutrophil count (ANC) <100/mm3, 9 (30%) developing ANC 100-500/mm3, and two (7%) with ANC 500-1000/mm3. Median ANC nadir was zero (range, 0-2800/mm3). The median time to ANC <1500/mm3, ANC <1000/mm3, ANC <500/mm3 and ANC <100/mm3 was 1 day, 2 days, 4 days, and 7 days post-CAR-T cell therapy, respectively. At day+30, the cumulative incidences of ANC <1500/mm3, ANC <500/mm3, ANC <100/mm3 were 93.3%, 90%, and 56.7%, respectively. The median duration of ANC <1500/mm3, ANC <500/mm3, and ANC <100/mm3 was 24 days, 6 days, and 3 days, respectively. At day +30, 3.7% of patients had persistent neutropenia with ANC <500/mm3, whereas 23.21% of patients experienced mild neutropenia (ANC <1500/mm3) at day +80 following CAR-T cell therapy. Nineteen patients received prophylactic G-CSF and 11 patients did not. No difference in infectious complications, and ICU admission was noted between both groups.Following CAR-T cell therapy, 86% (26/30) patients developed thrombocytopenia with two (7%) experiencing platelets <10,000/µL, 12 (40%) developing platelets 10,000-50,000/µL, and 12 (40%) with platelets 50,000-150,000/µL. Median platelet nadir was 57,000/µL (range, 2000-194,000). The median time to platelets <150,000/µL, <50,000/µL, and <10,000/µL was 1 day, 6 days, and 20 days post-CAR-T cell therapy, respectively. At day+30, the cumulative incidences of platelets <150,000/µL, platelets <50,000/µL, and platelets <10,000/µL were 83.3%, 40%, and 6.67%, respectively. The median duration of platelets <50,000/µL was 28.5 days and <150,000/µL was 192 days. At day +30, 50% of patients had persistent thrombocytopenia with platelets <50,000/µL, and 80.77% of patients had thrombocytopenia with platelets <150,000/µL. Sixty-one percent patients still experienced platelets <150,000/µL at day +80 following CAR-T cell therapy.Univariable analyses revealed that high dose of CAR-T cell was associated with decreased incidence of neutropenia (HR, 0.63; p=0.02), while absence of extra-nodal disease was associated with increased incidence of neutropenia (HR, 3.19; p=0.02). Moreover, patients with prior autoSCT had a lower likelihood of resolution of neutropenia (HR, 0.33; p=0.03), and those with multiple prior therapies had a lower likelihood of resolution of thrombocytopenia (HR, 0.36; p=0.002).Conclusion: Our study shows that a proportion of patients experienced prolonged hematological toxicity, and prior autoSCT and multiple lines of therapy were identified as risk factors. Prophylactic G-CSF did not appear to have any benefit on the prevention of neutropenia or infectious complications. [Display omitted] DisclosuresDeol: Kite, a Gilead Company: Consultancy. Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees.

Prolonged hematologic toxicity following treatment with chimeric antigen receptor T cells in patients with hematologic malignancies.

Chimeric antigen receptor T-cell therapy (CAR T) is a novel intervention for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) and other hematologic malignancies. However, it is associated with prolonged hematologic toxicity (PHT) that is unpredictable and can significantly impair patients' quality of life. Reported here is a single-center experience with PHT in adult patients with R/R DLBCL who received commercial CAR T-cell therapy between March 1, 2018 and May 30, 2020. Prolonged hematologic toxicity was defined as ≥ grade 3 neutropenia or thrombocytopenia at day +30 after CAR T-cell therapy. Of the 31 patients identified, 18 patients (58%) developed PHT. Patients with PHT had a shorter 1-year overall survival (OS) than patients without PHT (36% vs. 81%, P < .05). There were no differences in the median time to ANC recovery for those with PHT compared to patients without PHT (16 days vs. 15 days). Several risk factors were identified to be associated with PHT including CRS (P = .002), receipt of tocilizumab (P = .002) or steroids (P = .033), peak ferritin >5000 ng/ml (P = .048), peak C-reactive protein (CRP) > 100 mg/L (P = .007), and ferritin greater than the upper limit of normal at day +30. Seven patients with PHT underwent a bone marrow biopsy after CAR T-cell therapy; all showed complete aplasia or were hypocellular with cellularity ranging from <5% to 10%. These findings identify PHT as a significant toxicity associated with CAR T-cell therapy and highlight the critical need for further investigations to describe PHT in larger cohorts and identify standards for management of this condition.

Incidence and Causes of Prolonged Hematologic Toxicity after Chimeric Antigen Receptor T Cell Therapy: A City of Hope (COH) Experience

Incidence and Causes of Prolonged Hematologic Toxicity after Chimeric Antigen Receptor T Cell Therapy: A City of Hope (COH) Experience

INNV-14. ADJUVANT CHEMOTHERAPY AFTER SEVERE MYELOTOXICITY DURING TEMOZOLOMIDE CHEMORADIATION IN GLIOMAS. IT IS FEASIBILE?

Abstract INTRODUCTION Malignant gliomas are aggressive primitive brain tumor in adults. Today, the standard of care is Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ. TMZ treatment has been considered to have a low toxicity profile. However, during concomitant treatment some patient may develop a severe myelosuppression. This toxicity may be in some cases prolonged and lead to treatment discontinuation. METHODS We have retrospectively collected data from 5 Italian neuro-oncological centers, about glioma patients who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy with TMZ. The purpose of this study is to evaluate: percentage of patients receiving adjuvant chemotherapy after severe myelotoxicity; rate of toxicity observed during adjuvant chemotherapy. RESULTS 54 glioma patients who developed myelosuppression of grade 3 or 4 were considered. Histology was Glioblastoma in 45 patients (83%); 63% of patients were female. Myelotoxicity during concomitant phase occurred at a median of 4 weeks (range 1–8) from the start of treatment. After recovery of myelotoxicity 19 patients did not received any treatment while 35 (65%) were treated with chemotherapy (28 received standard TMZ, one TMZ with metronomic schedule, 2 lomustine and 4 other agents). Among patients treated with TMZ, 13 patients presented hematological toxicity grade 3–4 which required treatment discontinuation in 7 cases (20%). CONCLUSION the results of our study show that 80% of glioma patients presenting severe myelotoxicity during concomitant radiochemotherapy may be treated with maintenance TMZ after recovery of myelosuppression.

P14.83 Adjuvant chemotherapy after severe myelotoxicity during temozolomide chemoradiation in gliomas. It is feasibile? The talian Multicentric Study (AINO)

Abstract BACKGROUND Malignant gliomas are aggressive primitive brain tumor in adults. Today, the standard of care is Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ. TMZ treatment has been considered to have a low toxicity profile. However, during concomitant treatment some patient may develop a severe myelosuppression. This toxicity may be in some cases prolonged and lead to treatment discontinuation. MATERIAL AND METHODS We have retrospectively collected data from 5 italian neuro-oncological centers, about glioma patients who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy with TMZ. The purpouse of this study is to evaluate: percentage of patients receiving adjuvant chemotherapy after severe myelotoxicity; rate of toxicity observed during adjuvant chemotherapy. RESULTS 54 glioma patients who developed myelosuppression of grade 3 or 4 were considered. Hystology was Glioblastoma in 45 patients (83%); 63% of patients were female. Myelotoxicity during concomitant phase occurred at a median of 4 weeks (range 1–8) from the start of treatment.After recovery of myelotoxicity 19 patients did not received any treatment while 35 (65%) were treated with chemotherapy (28 received standard TMZ, one TMZ with metronomic schedule, 2 lomustine and 4 other agents). Among patients treated with TMZ, 13 patients presented hematological toxicity grade 3–4 which required treatment discontinuation in 7 cases (20%). CONCLUSION we observed that 80 % of glioma patients presenting severe myelotoxicity during concomitant radiochemotherapy may be treated with maintenance TMZ after blood value recovery.

PB1726 DOUBLE FLUDARABINE‐BASED INDUCTION AND INFECTIVE RISK: THE BOLOGNA EXPERIENCE.

Background:“3+7” represents the current standard of care for acute myeloid leukemia (AML). Fludarabine‐based regimens have limited application due to the absence of survival benefit and prolonged hematological toxicity after 2nd cycle. Infections in neutropenic patients represent an important cause of mortality and morbidity.Aims:To analyze the infective risk associated with intensive chemotherapy based on double‐FLAI induction.Methods:We retrospectively collected data of 40 consecutive adult patients with newly diagnosed AML treated with FLAI‐5 induction therapy (Fludarabine IV 25 mg/sqm/die days 1‐5, Cytarabine IV 2000 mg/sqm/die days 1‐5 and Idarubicin 10 mg/sqm/die on days 1, 3 and 5). Patients in complete remission (CR) proceeded to second FLAI‐5 followed by allogeneic transplant or chemotherapy consolidation. The incidence and type of infective events were collected in 36/40 patients. Patients were compared with a historical court of 39 patients treated with non‐fludarabine based induction. MRD was assessed by qRT‐PCR or WT1 gene expression. Data were harmonized using RedCap custom eCRFs.Results:Forty patients received FLAI‐5 from August 2015 to December 2018. Median age at diagnosis was 53 years (range 19‐66). According to NCCN‐2016 stratification criteria 12/40 (30%) patients were favorable, 10/40 (25%) intermediate and 17/40 (42.5%) high risk; one patient wasn’t evaluable. Thirty‐five patients (87.5%) achieved a CR after induction, 4 (10%) patients were refractory and 1 patient (2.5%) died during induction. Twenty‐nine of 40 patients were evaluable for MRD analysis and 15/29 (52%) patients achieved MRD negativity. Twenty‐two of the 35 patients in CR proceeded to 2nd FLAI‐5 chemotherapy regimen.At induction, patients recovered from neutropenia (ANC&gt; 500 x 109/L) after 21.5 days (range 13‐32) from the end of chemotherapy and reached platelet &gt; 20 x 109/L after a median of 16 days (range 10‐33). Patients spent a median of 33 nights in hospital (range 14‐61; historical control 35 nights, range 31‐42; p = ns). After 2nd cycle, median days for ANC and platelet recovery were 29 and 26 (range 16‐45 and 13‐60 respectively, historical control for ANC recovery 20 days, range 18‐25; p = 0.001). Median patients’ hospitalization was 39 nights (range 26‐55; historical control 32.5 nights, range 24‐47; p = 0.003).Patients and historical controls received same antimicrobial prophylaxis in induction and experienced respectively 33/36 (91.7%) and 36/39 (92.3%) infective events. Patients had a higher number of infections of unknown origin (15/33 vs 6/36, p. 002), and lower incidence of Gram‐positive isolates (4/12 vs 15/22, p = 0.002). Any‐mould infection rate was comparable in the two groups.Twenty‐seven of 36 patients and 22/39 controls proceeded to consolidation chemotherapy. Antimould prophylaxis was different, with patients receiving mainly posaconazole 17/27 (63 %), fluconazole 5/27 (18.5%), itraconazole 4/27 (14.8%) and voriconazole 1/27 (3.7%); while controls received posaconazole 4/22 (18.2%) fluconazole 5/22 (22.7%), itraconazole 12/22 (54.5%) and voriconazole 1/22 (4.5%). Twenty‐two of 27 patients (81.5%) and 17/22 (77.3%) in controls had an infection. Three patients of 27 had a probable mould infection and 1 possible, compared to 1 proven mould infection and 1 possible in the 22 controls (any‐mould infection 4/27 vs 2/22).Summary/Conclusion:In our experience FLAI‐5 is associated with high CR rates, but prolonged neutropenia and hospitalization after 1st consolidation. However, this doesn’t translate in a higher infection risk in this set of patients.

MDS AS A CAUSE FOR PROLONGED HEMATOLOGIC TOXICITY AFTER TREATMENT WITH CD19 TARGETED CAR‐T CELL THERAPY IN PATIENTS WITH RELAPSED REFRACTORY LYMPHOMA

Introduction: The advent of adoptive cellular therapy utilizing autologous T cells expressing chimeric antigen receptors (CAR-T) against CD19 has revolutionized relapsed and refractory B cell lymphoma treatment. CAR-T cell therapy, however, is not without toxicity. Other than cytokine release syndrome and neurotoxicity, hematologic toxicity occurs commonly as well. Grade 3 and above prolonged neutropenia and thrombocytopenia (longer than 4 weeks since T cell infusion) was seen in 15 to 40% and 18 to 40% of patients treated with CD19 CAR T cells in clinical trials respectively. The exact mechanism underlying the pathogenesis of prolonged hematologic toxicity in CAR-T cell therapy is not well understood. Interestingly, we identified four cases of prolonged cytopenias after CAR-T cell therapy due to the presence of myelodysplastic syndrome in patients receiving this treatment for relapsed refractory B cell lymphoma. Methods: We performed a retrospective review of four patients with relapsed refractory aggressive B cell lymphoma treated at our institution with CD19 directed autologous CAR-T cells. Results: Median age was 74 (range: 57-76). Two patients had GCB type, 2 had non-GCB type DLBCL. The median number of lines of therapy prior to CAR-T cell therapy was 5. All four patients had prior autologous stem cell transplantation. Median time to MDS diagnosis from CAR T infusion was 3 months (range: 2 to 3). One patient developed MDS after additional chemotherapy was given for relapsed disease. One patient had evidence of a dysplastic clone prior to CAR-T cell therapy. The remaining two patients did not have evidence of MDS until immediately after CAR-T cell therapy. Two patients developed severe CRS requiring tocilizumab and corticosteroids. One patient showed partial response to CAR-T cell therapy, while three others achieved CR, two of which have since relapsed. Discussion: We identified four patients with prolonged hematologic toxicity after CAR-T cell therapy due to MDS. These patients have multiple risk factors for the development of MDS including advanced age, and heavy pretreatment. In fact, one patient had evidence of MDS prior to CAR-T cell therapy, underscoring the potential benefit of providing CAR-T cell therapy earlier in the course of treatment. In addition, our findings suggest that a bone marrow study should be performed in patients with prolonged cytopenias post CAR T cell therapy. It is not clear if there is any direct contribution of CAR T cells and the resulting immune system disturbance to the development of MDS. Long term follow up of all patients receiving CAR T cell therapy is therefore crucial to assessment true incidence of MDS and establish association. Keywords: B-cell lymphoma; CD19. Disclosures: Herrera, A: Consultant Advisory Role: Gilead. Siddiqi, T: Consultant Advisory Role: Juno Therapeutics. Budde, E: Consultant Advisory Role: Gilead. 480 – WITHDRAWN

Good tolerability of maintenance temozolomide in glioblastoma patients after severe hematological toxicity during concomitant radiotherapy and temozolomide treatment

Glioblastoma is the most common and aggressive primitive brain tumor in adults. Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ has become the standard treatment. Although TMZ treatment has been considered to have a low toxicity profile, studies have noted the development of a severe myelosuppression, especially during the concomitant treatment; this toxicity may in some cases be prolonged and consequently treatment must be definitively discontinued. We analyzed two cases treated at our oncological center who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy treatment with TMZ. Hypothesizing that radiation therapy and daily TMZ could be the major causes of severe hematological toxicity during the concomitant phase, we decided to treat both patients with maintenance TMZ at the time of recovery of hematological values. Patients showed good tolerability without important myelosuppression. In conclusion, we suggest that glioblastoma patients with severe myelotoxicity during daily TMZ and radiation therapy be treated with maintenance TMZ at the time of blood value recovery.

Safety and Efficacy of Addition of Pegylated Interferon alpha2b to Standard Dose Dasatinib in Newly Diagnosed Chronic Phase CML Patients

▪Rationale: Dasatinib (DAS) and interferon have different modes of action and may have synergistic activity in CML, due to both antineoplastic and immunostimulatory mechanisms. Addition of pegylated interferon (PegIFN) to imatinib therapy in CP-CML has in previous clinical trials (French SPIRIT and NordCML002) resulted in deeper molecular responses. Thus, an optimal combination of DAS and PegIFN may increase the proportion of patients who reach deep molecular response with potential for treatment-free remission (TFR).Design: Newly diagnosed CP-CML patients were treated with DAS (Sprycel, BMS) 100 mg OD as single drug for three months. Thereafter weekly subcutaneous injections of Peg-IFN α2b (PegIntron, MSD) were added to DAS; from end of month 3 (M3) to M6, 15µg/week, thereafter 25µg/week until M15. Primary end points were safety and the rate of MMR at M12. The doses of PegIFN were lower than in the SPIRIT and NordCML002 studies to increase adherence.Population: Forty patients were included at 14 university centers. One patient was lost to follow-up after M6. All patients were included in analysis up to M12. Mean and median age was 48 years (range 19-71). The proportions of high risk patients were 25% (Sokal), 15% (Hasford), and 15% (EUTOS).Safety and dosing: Treatment was well tolerated with expected DAS and PegIFN related side effects. Six patients had seven serious adverse events (AEs), all hospitalizations. 1 episode each of bradycardia/atrial fibrillation (possibly PegIFN-related), headache (DAS), fever (PegIFN), anaphylaxis-like reaction (PegIFN), fever/malaise/headache (PegIFN), pneumonia and a knee effusion (both unrelated). One pleural effusion occurred (grade 2, 3%). Grade 3-4 neutropenia and thrombocytopenia occurred in 6 and 9 patients respectively. Prolonged hematological toxicity (>2 months) occurred in 8 patients, causing dosing problems in 5. One patient suffered grade 3 depression. Grade 3 flu-like symptoms occurred in 2 patients. One patient had lipase elevation grade 3 and one patient developed hypothyroidism attributed to PegIFN. Grade 2 dermal AEs like rash and acne occurred in about 20%, attributable to both drugs. 94% (DAS) and 76% (PegIFN) of assigned dose was given. Dose reductions occurred in 19 patients for DAS and 20 patients for PegIFN. Two patients discontinued DAS and switched to nilotinib, 1 for headache at M3 and 1 at M12 for lack of efficacy/hematological toxicity. Two patients could not start PegIFN for hematological toxicity (one lost to follow-up after M6). PegIFN was discontinued because of bradycardia/atrial fibrillation (1 patient), anaphylaxis (1 patient), flu-like syndrome (2 patients) and long-term hematological toxicity (2 patients). At 12 months 31/38 pats (82%) were still on PegIFN, a higher proportion than in the French Spirit or NordCML002 studies.Efficacy: We have used the DAS arm of the Dasision study (Kantarjian NEJM 2010) as a historical control. Early response at M3 was very similar between studies. In the present and the Dasision cohorts respectively, 18% vs 16% missed the 10% BCR-ABLIS landmark, 66% vs 56% achieved a CCyR and 8% vs 8% achieved MMR. At M6, three months after introduction of PegIFN, a steep increase in MMR rate was observed compared with Dasision. This was also reflected in deep responses, MR4.0 (see tables) and MR4.5 at M12, 18% vs 5%. The primary efficacy endpoint was MMR at M12, 82% vs 46%. Table 1MMRDAS+PegIFN (%)DAS (Dasision)(%)Difference (%)M3880M6532726M9663927M12824636Table 2MR4.0DAS+PegIFN (%)DAS (Dasision) (%)Difference (%)M3303M620614M938830M12481236Progressions and treatment failure defined by ELN 2013: Failures: No progression was noted. At M3, 2 patients still had >95% Ph+ metaphases (MF). At M6, four patients (11%) had > 35% Ph+MF or >10% BCR-ABL levels. At M12, one patient failed CCgR and two more patients failed <1% BCR-ABL. No BCR-ABL mutations were detected in "failure" patients.Conclusion: The combination of DAS and low dose PegIFN could be safely administered in newly diagnosed CP CML. No unexpected autoimmune phenomena were observed, and pleural effusions were rare. Efficacy appears very promising with high early MMR rates and deep molecular responses. A randomized comparison DAS +/- PegIFN is warranted.Support: Study drug from BMS and MSD. Grant from BMS. [Display omitted] DisclosuresHjorth-Hansen:Ariad: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Off Label Use: Dasatinib and Pegylated IFN combination in CML. Richter:Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding.

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia

AbstractThe safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135.

Lenalidomide Plus Melphalan Without Prednisone for Previously Untreated Older Patients With Multiple Myeloma: A Phase II Trial

We conducted a phase II trial that evaluated the tolerability and efficacy of combining lenalidomide with melphalan in previously untreated patients with multiple myeloma who were not candidates for autologous stem cell transplantation. After a run-in phase of 6 patients, we planned to conduct a randomized phase II selection-design trial that assessed 2 dose levels of lenalidomide, given days 1 to 21, combined with melphalan, given days 1 to 4, and every 28 days. Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). Coprimary endpoints were the frequency of dose-limiting Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). toxicities (DLT) and complete response (CR). Four patients received M9L10; all experienced DLTs, which resulted in closure of this cohort. When using the same schedule, we then sequentially tested M6L10 (melphalan 6 mg/m(2) on days 1 to 4 and lenalidomide 10 mg/d on days 1 to 21 every 28 days) (6 patients), M4L15 (melphalan 4 mg/m(2) on days 1 to 4 and lenalidomide 15 mg/d on days 1 to 21 every 28 days) (6 patients), and M5L10 (melphalan 5 mg/m(2) days 1 to 4 and lenalidomide 10 mg/d days 1 to 21 every 28 days) (34 patients). In each cohort, the DLT endpoint was reached because of severe and prolonged hematologic toxicity. At the final dose level, M5L10, 20 of 27 patients experienced DLTs within their first 3 cycles; among 10 patients who received at least 6 cycles, none achieved a CR. Combining lenalidomide plus melphalan without prednisone is associated with substantial hematologic toxicity that precludes cyclical administration of adequate drug doses.

Bortezomib, Dexamethasone, and High-Dose Melphalan as Conditioning for Stem Cell Transplantation in Young Japanese Multiple Myeloma Patients: A Pilot Study

Autologous stem cell transplantation is recommended for younger patients with newly diagnosed multiple myeloma because of a high complete response rate and better survival. Bortezomib shows a synergistic effect with melphalan and has no prolonged hematologic toxicity, and the complete response rate after autologous stem cell transplantation is improved by combining bortezomib with melphalan for conditioning. Twelve patients were enrolled in a phase 2 study between February and November 2010, receiving bortezomib (1mg/m(2)×4), dexamethasone (20mg/body×8), and melphalan (200mg/m(2)) for conditioning. No toxic deaths occurred. Neutrophils (absolute neutrophil count ≥0.5×10(9)/L) and platelets (≥20×10(9)/L without transfusion) recovered after a median of 5days (range: 4-6days) and 7days (range: 4-8days), respectively. No patient was admitted for exacerbation of peripheral neuropathy. Four patients obtained a stringent complete response, three patients obtained a complete response, and three patients showed a very good partial response. These results suggest that this conditioning regimen is safe and promising for young Japanese multiple myeloma patients. A prospective multicenter trial of this regimen combined with suitable induction and consolidation therapy should be performed.

A CASE OF ATYPICAL PROLONGED HEMATOLOGIC TOXICITY WITH AZACITIDINE IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), REVIEW OF LITERATURE AND A PROPOSAL OF MANAGEMENT

Hypomethylating drugs are useful and have been approved for the treatment of myelodysplastic syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS, have included only a small number of patients with CMML, and there are just a few specific reports on CMML patients. The Azacitidine is actually authorised for the treatment of CMML patients with 10–29% marrow blasts without myeloproliferative disorder, who are not eligible for haematopoietic stem cell transplantation. This hypomethylating agent in MDS is known for causing transient cytopenias, most often occurring during the first 2 cycles. Here we report a case of an atypical delayed and prolonged hematologic toxicity during Azacitidine treatment in a CMML patient; furthermore we also reviewed the literature regarding the efficacy of the drug and the management of hematologic adverse effects, in term of dose adjustments or alternative schedule of administration, in specific CMML setting.

Clofarabine in Combination with a Standard Remission Induction Regimen (AraC and idarubicin) in Patients with Previously Untreated Intermediate and Bad Risk Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS):Phase I Results of An Ongoing Phase I/II Study of the EORTC-LG and GIMEMA(EORTC GIMEMA 06061/AML-14A trial)

Abstract 2610 Introduction:Remission induction treatment in previously untreated intermediate/bad risk AML or high risk MDS needs continuous improvement. Clofarabine is a nucleoside analog with proven activity in acute leukemias. The aim of the study was to determine the recommended/maximum tolerated dose (MTD) of Clofarabine when administered with standard remission induction regimen (Ara-C and Idarubicin) in patients suffering from AML/MDS. Methods:This open label, 2-arm, multi-center, phase I trial included adult patients (pts) with previously untreated intermediate/bad risk AML or high risk MDS. All FAB subtypes except M3 and the cytogenetic groups, t(8;21) or inv(16) with WBC<100×109/l, were eligible. Pts with blast crisis of CML or CNS leukemia were excluded. Arm A: 1h infusion Clofarabine (10 mg/m2/d and 15 mg/m2/d) on d2, d4, d6, d8, d10; Ara-C continuous infusion (c.i.): 100 mg/m2/d on d1-d10, Idarubicin (i.v): 10 mg/m2/d, on d1, d3, d5. Arm B: push injection Clofarabine (10 mg/m2/d and 15 mg/m2/d on d2, d4, d6, d8, d10); Ara-C and Idarubicin same regimen as in arm A. A minimum of 3 pts per arm were to be included at each dose level. The next dose level was visited if none of the first 3 patients experienced a Dose Limiting Toxicity (DLT) at a certain dose level. DLT was defined as treatment-related adverse events: non-hematological grade III-IV toxicity (CTCAE 3.0) occurring during 8 weeks (except grade III events resolving to grade < III within 4 weeks) after the start of the remission induction, and/or hematological toxicity defined as bone marrow hypoplasia leading to neutrophil or platelet recovery (ANC > 0.5 × 109/l and platelets >50 × 109/l) later than 8 weeks after start of remission induction. If 1 out of the first 3 pts experienced a DLT, 3 additional pts were added (a maximum of 6 pts per dose level) in order to ensure the safety profile of this dose level. If a second patient experienced a DLT, no further pts were entered at that particular dose level. Dose escalation stopped and additional pts included at the previous lower dose to have a minimum of 6 pts treated at the recommended dose. Results:25 pts have been entered into this phase I part in 3 participating sites. WHO PS status was 0 (N=16), 1 (N=8) or 2 (N=1). Age range was 25–60 years (median 55 years). 20 pts had de novo AML, 3 pts had secondary AML, 2 pts had de novo MDS (WHO RAEB-2). 7 pts had high cytogenetic risk features. In arm A and in arm B 10 mg/m2/d Clofarabine, and in arm A 15 mg/m2/d Clofarabine 6 pts each have been included. In arm B 15 mg/m2/d Clofarabine 7 pts were included, as one patient was substituted since she received 60% of total dose of Clofarabine and refused further treatment with Clofarabine due to related adverse event. All 25 pts were evaluable for DLT analysis. Overall, 5 pts with DLTs were observed: 1 in Arm A 10mg/m2/d Clofarabine, 3 in Arm A 15 mg/m2/d Clofarabine, 1 in Arm B 15 mg/m2/d Clofarabine. One patient with prolonged hematological toxicity as DLT reported in Arm A 10mg/m2/d Clofarabine. Two deaths in cytopenia/aplasia and one toxic death following sepsis/multiorgan failure have been reported as DLTs in 3 patients in both Arm A and B 15 mg/m2/d Clofarabine. The 5th patient had grade 4 anorexia, diarrhea, infection, prolonged hypoplasia and grade 3 confusion which classified as DLT in Arm A 15 mg/m2/d Clofarabine. In addition, three pts in the 15 mg/m2/d Clofarabine arms needed to be withdrawn from Clofarabine due to adverse events not classified as DLT. Main toxicity was bone marrow toxicity resulting in prolonged aplasia. Out of 25 pts, complete remission (CR) following induction 1/2 has been achieved in 19 pts: in 10/12 pts using 10 mg/m2/d Clofarabine (5 pts each in Arm A and Arm B) and in 9/13 pts using 15 mg/m2/d Clofarabine (4 pts in Arm A and 5 pts in Arm B). In addition CR with incomplete blood count recovery (CRi) following induction 1/2 was observed in 2 pts: 1 in Arm A 10 mg/m2/d Clofarabine and 1 in Arm B 15 mg/m2/d Clofarabine. Conclusion:Infusion of 15 mg/m2/d Clofarabine resulted in a high rate of DLTs (4/13 pts) and early treatment withdrawals (3/13 pts). The infusion of 10 mg/m2/d Clofarabine had an acceptable rate of DLTs (1/12 pts), no early treatment withdrawals occurred, and a high CR/CRi rate (11/12 pts) was observed. Therefore the MTD of Clofarabine in combination with Ara-C and Idarubicin is defined at 10 mg/m2/d and will be the recommended dose for the phase II part of this study. Disclosures:Willemze:Genzyme: member advisory committee clofarabine. Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.

Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myélome (IFM)

AbstractAutologous stem cell transplantation (ASCT) is recommended for younger patients with newly diagnosed multiple myeloma. Achieving complete response (CR) or at least very good partial response (VGPR) is a major prognostic factor for survival with 20% to 30% of patients achieving CR after ASCT. Bortezomib has shown synergistic effects with melphalan and no prolonged hematologic toxicity. In this Intergroupe Francophone du Myélome (IFM) phase 2 study, 54 untreated patients were enrolled between July and December 2007 to receive bortezomib (1 mg/m2 × 4) and melphalan (200 mg/m2) as conditioning regimen (Bor-HDM). Overall, 70% of patients achieved at least VGPR, including 17 patients with CR (32%) after ASCT. No toxic deaths were observed. Bortezomib did not increase hematologic toxicity. Only 1 grade 3 to 4 peripheral neuropathy was reported. A matched control analysis was conducted comparing our cohort with patients from the IFM 2005-01 trial (HDM alone). Patients were matched for response to induction therapy and type of induction: CR was higher in the Bor-HDM group (35% vs 11%; P = .001), regardless of induction therapy. These results suggest that Bor-HDM is a safe and promising conditioning regimen. Randomized studies are needed to assess whether this conditioning regimen is superior to HDM alone. This trial was registered at www.clinicaltrials.gov as NCT00642395.