Hepatic and Metabolic Complications In Adult Patients With Acute Lymphoblastic Leukemia (ALL) Treated With Asparaginase-Containing Combination Chemotherapy: A Single Center Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1405-1405
Author(s):  
Jason N. Barreto ◽  
Kristen B. McCullough ◽  
Candy S Peskey ◽  
Louis Letendre ◽  
William Hogan ◽  
...  
Keyword(s):  
Side Effects ◽  
Dose Reduction ◽  
Combination Chemotherapy ◽  
Adult Patients ◽  
Comparable Efficacy ◽  
Hepatic Toxicity ◽  
Single Center ◽  
Confounding Variables ◽  
Grade 3 ◽  
The Impact

Abstract Background L-asparaginase (LASP) therapy in adults is associated with frequent hepatic and metabolic side effects, often resulting in dose adjustments and omissions. Pegylated asparaginase (PEGASP) substituted for LASP improves convenience of administration with comparable efficacy; however, adverse event (AE) management remains challenging. The incidence and management of LASP- and PEGASP-induced metabolic and hepatic complications in adult ALL patients is not well defined. Methods This single center, retrospective, observational study was approved by the Mayo Clinic Institutional Review Board. Consecutive adult patients with a confirmed diagnosis of ALL receiving LASP or PEGASP containing chemotherapy regimens between January 2000 and October 2012 were evaluated. Patients were followed up to 60 days after the last LASP or PEGASP dose for development of biochemical and clinical pancreatitis, hypertriglyceridemia and hepatotoxicity. Hyperglycemia was not analyzed due to confounding variables, such as concomitant corticosteroid administration. AEs were graded as per the National Cancer Institute Common Terminology Criteria (CTCAE) version 4.03. Analysis was performed using Cox proportional hazard models with odds ratios (with 95% confidence intervals) reported to demonstrate the strength of association between group and AE rate. Results Of 74 adult patients, 54 (73%) met inclusion criteria. History of dyslipidemia, diabetes mellitus, cholelithiasis and coronary artery disease was documented at baseline in 13 (24%), 4 (7%), 4 (7%) and 10 (19%) patients, respectively. Twenty eight (52%) patients received LASP, 22 (41%) received PEGASP and 4 (7%) received both. A total of 399 doses including 335 (84%) LASP and 64 (16%) PEGASP were administered. Distribution based on treatment schedules was as follows; CALGB 9111 (n=20 (37%), Larson et al, 1998), E2993 (n=13 (24%), Goldstone et al, 2008), C10403 (n=9 (17%), NLM: NCT00558519), CCG 1941 (n=7 (13%), Gaynon et al, 2006) and Augmented Hyper-CVAD (n=5 (9%), Faderl et al,2011). Six (11%), 20 (37%), and 53 (98%) patients experienced pancreatic, lipid (hypertriglyceridemia) and hepatic adverse events, respectively. In this group, CTCAE grade 3/4 AEs occurred in 0 (0%), 8 (15%), and 28 (52%) patients, respectively. No deaths were directly related to these complications. Patients receiving PEGASP were more likely to experience AE of any CTCAE grade (OR 11.5, 95% CI 4.4-30.3, p < 0.0001), including grade3/4 AEs (OR 27.9, 95% CI 11.4-68.2, p < 0.0001) in comparison to those receiving LASP. All cases of pancreatitis manifested as biochemical elevation in pancreatic enzymes, and were either grade 1 (n=4, 67%) or grade 2 (n=2, 33%). All patients were managed conservatively. Management of hypertriglyceridemia was heterogeneous across all grades and included observation (n=11, 55%), non-pharmacologic interventions (n=1, 5%), medication management (n=4, 20%) and combined strategies (n=4, 20%). The most common practice was a combination of fibrate derivatives (fenofibrate) and fish oil (n= 5). One patient with a peak triglyceride level of 2285 mg/dL was placed on an insulin/dextrose infusion for 4 days. Hepatic toxicity manifested as CTCAE grade 3/4 transaminitis in 13 (24%) patients, hyperbilirubinemia in 4 (7%) patients and both in 11 (20%) patients. Temporal correlation was used to best distinguish confounding variables including possible hepatoxicity from azole antifungals and other drugs. Management of hepatic toxicity included delay in dosing, subsequent LASP or PEGASP dose reduction and laboratory monitoring until resolution. Overall, deviations in LASP or PEGASP administration were documented in 18 (33%) patients due to metabolic or hepatic AEs. Eight (15%) patients required omission of at least 1 dose, 7 (13%) experienced delays of administration and 7 (13%) needed a dose reduction. Conclusion PEGASP administration resulted in significantly higher AE rates in comparison to LASP and this significance was retained when comparing AEs of CTCAE grade 3 and 4. Given the growing trend of using PEGASP combination chemotherapy in adults with ALL, a detailed analysis looking at the increase in side effects, their consequences (delayed tereatment and dose reductions) and the impact of these factors on disease remission and survival is needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110026
Author(s):  
Chinar R. Parikh ◽  
Jaya K. Ponnampalam ◽  
George Seligmann ◽  
Leda Coelewij ◽  
Ines Pineda-Torra ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Efficacy ◽  
Inflammatory Arthritis ◽  
Biologic Agents ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Biologic Drugs ◽  
Therapeutic Implications ◽  
The Impact ◽  
First Time

The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved disease outcomes compared with the pre-biologic era. However, immunogenicity to biologic agents, characterised by an immune reaction leading to the production of anti-drug antibodies (ADAs), can negatively impact the therapeutic efficacy of biologic drugs and induce side effects to treatment. This review explores for the first time the impact of immunogenicity against all licensed biologic treatments currently used in inflammatory arthritis across age, and will examine any significant differences between ADA prevalence, titres and timing of development, as well as ADA impact on therapeutic drug levels, clinical efficacy and side effects between paediatric and adult patients. In addition, we will investigate factors associated with differences in immunogenicity across biologic agents used in inflammatory arthritis, and their potential therapeutic implications.

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

2021 ◽  
pp. 107815522110179
Author(s):  
Olivia R Court
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Free Survival ◽  
Length Of Treatment ◽  
Common Grade ◽  
Grade 3 ◽  
The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

scholarly journals Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1(PD-L1) Inhibitor Therapy in HIV Patients with Advanced Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Shahla Bari ◽  
Jameel Muzaffar ◽  
Austin Chan ◽  
Sanjay R. Jain ◽  
Ahmad M. Haider ◽  
...  
Keyword(s):  
Side Effects ◽  
Advanced Cancer ◽  
Infectious Complications ◽  
Response To Therapy ◽  
Comparable Efficacy ◽  
Hiv Viral Load ◽  
Hiv Patients ◽  
Hiv Rna ◽  
Programmed Death ◽  
The Impact

Due to HAART and consequent decline in mortality from infectious complications, HIV patients have an increasing burden of non-AIDS defining cancers. Data on their safety and efficacy is unknown as these patients were excluded from clinical trials due to concern of unforeseen side effects. Objectives. The main objective of our study was to evaluate the efficacy and safety profile of PD-1 and PD-L1 inhibitors in HIV patients being treated for advanced cancers and to assess the impact of these drugs on HIV status of the patients specifically CD4 count and HIV viral load. Materials and Methods. This was a retrospective analysis of data of 17 patients HIV treated with one of the PD-1/PD-L1 inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, or Avelumab) for advanced cancer. Results. 10 out of 17 patients responded to therapy. 7 patients, all of whom had shown response to therapy, were alive and 4 were still on checkpoint inhibitor. 10 patients including all 7 nonresponders had died. Responders had minimum of 15 weeks of response while one had ongoing continued response at 34 weeks. Side effects were seen in 7 patients and only one patient needed cessation of therapy. CD4 counts were stable on treatment while HIV RNA remained undetectable. Conclusion. PD-1 and PD-L1 inhibitors appear to have comparable efficacy and tolerable side effect profile and have no effect on HIV markers when used in HIV patients with advanced cancers.

Weekly Low Dose Epirubicin in Elderly Cancer Patients

1996 ◽  
Vol 82 (4) ◽  
pp. 369-371 ◽  
Author(s):  
Dario Nicolella ◽  
Giuseppe Grimaldi ◽  
Giuseppe Colantuoni ◽  
Mario Belli ◽  
Giuseppe Frasci ◽  
...  
Keyword(s):  
Side Effects ◽  
Elderly Patients ◽  
Cancer Patients ◽  
Combination Chemotherapy ◽  
Clinical Studies ◽  
Low Dose ◽  
Performance Status ◽  
Elderly Cancer Patients ◽  
Grade 3 ◽  
Severe Mucositis

Aims and background The treatment of elderly patients with metastatic solid tumours is still a debated problem. Patients over 75 years are generally excluded from combination chemotherapy trials because of higher toxicity. Several clinical studies have shown that weekly low dose epirubicin is a well tolerated and effective treatment for elderly cancer patients (breast, prostate, lung). Methods We report a study of patients aged between 75 and 85 years affected by metastatic anthracyclines-sensible carcinomas, to assess the tolerance of epirubicin given weekly at a dose of 25 mg/m2. Results 25 patients (13 males, 12 females; ECOG P.S. 0-2) entered the study and were evaluable for side effects. One-hundred and ninety-six cycles of therapy have been administered. Side effects were never severe. Mucositis (9 patients), leucopenia (7 patients), anemia (5 patients) were usually of grade 1 or 2. Grade 1 cardiotoxicity (tachycardia) was observed in only one case. Grade 3 toxicity consisted in anemia (1 patient) and mucositis (1 patient), while grade 4 toxicity never occurred. Nineteen patients were evaluable for response: 0 CR, 4 PR (1 lung, 3 breast), 8 SD (3 lung, 3 breast, 2 prostate) have been observed. Compliance was encouraging and the majority of patients showed a decrease in symptoms and an improvement in performance status. Conclusions Weekly low-dose epirubicin is a very well tolerated treatment in elderly cancer patients. In view of the negligible toxicity encountered, it could be of utility to test this regimen in patients aged 75 years or older, affected by anthracyclines-sensible metastatic tumors, also to assess activity.

A retrospective safety analysis of adult patients treated with high-dose methotrexate for osteosarcoma in Stockholm, Sweden.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10083-10083 ◽  
Author(s):  
Daniel Alm ◽  
Christina Linder Stragliotto ◽  
Annika Folin ◽  
Jonas Bergh ◽  
Theodoros Foukakis
Keyword(s):  
Oral Mucositis ◽  
Blood Concentration ◽  
Renal Toxicity ◽  
Adult Patients ◽  
Bleeding Complications ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Hepatic Toxicity ◽  
Dose Methotrexate ◽  
Grade 3

10083 Background: Patients with osteosarcoma are routinely treated with pre- and post-operative chemotherapy that includes high-dose methotrexate. The treatment is associated with a risk of severe renal and hepatic toxicity. Methods: All patients with osteosarcoma that had received at least one cycle of high-dose methotrexate at the adult oncology department, Karolinska University Hospital were retrospectively identified. Treatment toxicity, including hematologic, renal, hepatic toxicity, infections and oral mucositis were registered and graded according to CTCAE v 4.0. A possible relationship between methotrexate blood concentration and toxicity was investigated. Results: Sixteen eligible patients that had received a total of 103 cycles of high-dose methotrexate were identified. Ten patients experienced a severe hepatic toxicity, (Grade 3, n=5 and Grade 4, n=5). Grade 3 renal toxicity was seen in one patient and although reversible, it led to treatment interruption. Reversible, grade 2 elavation of serum creatinine occured in 5 cases. Four grade 3 infections were seen in 2 patients and 8 patients had at least one occurrence of Grade 3 oral mucositis. Thrombocytopenia was a common event (Grade 3, n=5 and Grade 4, n=2) but no severe bleeding complications were observed. One patient died as a result of multi-organ failure two days after methotrexate administration. Methotrexate blood concentration at 24 hours from administration could predict for renal toxicity (p<0.005, by chi-square test), but not for other toxicity. Conclusions: High-dose methotrexate in adult patients with osteosarcoma was frequently associated with severe, however reversible toxicity.

The impact of kidney function on the efficacy and safety of pazopanib in metastatic renal cell carcinoma (mRCC) patients: CORE-URO-01 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16063-e16063
Author(s):  
Maria Giuseppa Vitale ◽  
Cristina Masini ◽  
Giuseppe Procopio ◽  
Ugo De Giorgi ◽  
Sebastiano Buti ◽  
...  
Keyword(s):  
Renal Function ◽  
Side Effects ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Therapy Initiation ◽  
Frequent Monitoring ◽  
Group 2 ◽  
Grade 3 ◽  
The Impact ◽  
Group 1

e16063 Background: Pazopanibhas been approved for treatment of patients (pts) with mRCC based on the prospective randomized trial that enrolled only pts with adequate renal parameters. There are no data on the toxicity profile and efficacy of pazopanib in pts with renal insufficiency (RI).The aim of this study is to investigate the effect of renal function on treatment outcomes in pts treated with pazopanib for mRCC. Methods: We retrospectively analyzed the data of the mRCC pts treated with pazopanib with respect to renal function in eleven Italian institutions from January 2010 to June 2016. Baseline glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula at the time of therapy initiation. Pts with MDRD < 60 mL/min/1.73 m2 (group 1) were compared with pts with MDRD ≥60 mL/min/1.73 m2(group 2) in terms of response rates, progression free survival (PFS), overall survival (OS) and side effects. Results: One hundred and twenty-ninepts with mRCC were included in this study: 70 pts in group 1 and 59 pts in group 2. 67% of pts were male, median age was 66 years (34-83) and median CrCl was 49 ml/min (6.3-59.5) in group 1. In group 2, 64% of pts were male, median age was 65 years (38-80), and median CrCl was 64 ml/min (58.1-137.1) Pts with MDRD < 60 were more likely to have had a previous nephrectomy (84.3% vs 79.7%). No difference between the 2 groups was observed in terms of outcomes: PFS was 9.6 months (0.6–56.9) and 9.0 months (0.4–60.1), OS was 16.1 months (1.3–56.9) and 17.0 months (1.2–60.1), for MDRD < 60 group and MDRD ≥60 respectively. The disease control rate was 85.8% in group 1, and 72.9% in group 2. About grade 1-2 toxicity, no difference between the 2 groups was reported (67.1% vs 67.8%) while a higher incidence of grade 3-4 toxicity was evident in the group 1 (25.7% vs 18.6%). Conclusions: RI was commonly observed in pts with mRCC. Renal function at therapy initiation does not adversely affect the efficacy and safety of pazopanib. More frequent monitoring of side-effects in patients with RI is recommended.

scholarly journals Prognostic Factors in Patients with Septic Disseminated Intravascular Coagulation Treated with Thrombomodulin: The Effect of Reduced Thrombomodulin Dose; a Single-center, Retrospective, Observational Study

2021 ◽  
Author(s):  
Yoshihiro Nishita ◽  
Masatoshi Taga ◽  
Masaru Sakurai ◽  
Yoshitsugu Iinuma ◽  
Togen Masauji
Keyword(s):  
Prognostic Factors ◽  
Side Effects ◽  
Renal Dysfunction ◽  
Dose Reduction ◽  
Disseminated Intravascular Coagulation ◽  
Sofa Score ◽  
Single Center ◽  
Intravascular Coagulation ◽  
Reduced Dose ◽  
All Cause Mortality

Abstract Background: Human soluble recombinant thrombomodulin (TM alfa), a treatment for septic Disseminated intravascular coagulation (DIC), is recommended for patients with severe renal dysfunction in reduced doses. However, no studies have examined yet how dose reduction affects clinical efficacy. In this study, we investigated the significance of the TM alfa dose as a prognostic factor in clarifying the clinical background factors related to the clinical effect of TM alfa in patients with septic DIC.Methods: This study involved 102 patients with septic DIC admitted to a single-center intensive care unit between April 2013 and March 2020, receiving TM alfa. The following factors were retrospectively collected from the medical records of the target patients: (1) patient background, (2) sequential organ failure assessment (SOFA) score, (3) Japanese Association for Acute Medicine DIC diagnostic criteria score, (4) DIC treatment information, (5) TM alfa dose per bodyweight (normal dose: 0.06 mg/kg or reduced dose: 0.02 mg/kg), (6) DIC resolution within 7 days after the start of TM alfa administration (DIC resolution), (7) all deaths within 30 days after the start of TM alfa administration (30-days-all-cause mortality), (8) presence or absence of new hemorrhagic side effects after the start of TM alfa administration. Multiple logistic regression analysis was used to assess factors associated with DIC resolution and 30-days-all-cause mortality.Results: The SOFA score (odds ratio: 95% confidence interval, 0.76: 0.66–0.89), pneumonia (0.24: 0.08–0.75), and reduced dose administration of TM alfa (0.23: 0.08–0.66) were independent of and negatively related to the DIC resolution. For the 30-days-all-cause mortality, the SOFA score (1.66: 1.31–2.09), pneumonia (9.50: 2.49–36.25), and TM alfa dose reduction (3.52: 1.06–11.69) were independent, poor prognostic factors. We found no association between the hemorrhagic side effects and the TM alfa dose per bodyweight.Conclusions: The reduced dose of TM alfa for patients with severe renal dysfunction was observed to be an influential factor for DIC resolution and 30-day all-cause mortality in addition to SOFA score and pneumonia. Further studies are required in the future to verify this finding.

scholarly journals Periorbital dermatitis in patients receiving docetaxel in combination chemotherapy

2019 ◽  
Vol 12 (7) ◽  
pp. e230023 ◽  
Author(s):  
Mika Michelle Tabata ◽  
Bernice Kwong
Keyword(s):  
Side Effects ◽  
Cancer Therapy ◽  
Dose Reduction ◽  
Combination Chemotherapy ◽  
Cutaneous Side Effects ◽  
Cutaneous Reactions ◽  
Chemotherapy Dose

Recognition of new cutaneous side effects of combination chemotherapy can help prevent unnecessary cessation or reduction of cancer therapy. Periorbital rash has not been found with docetaxel alone, but here, we report it as a result of combination chemotherapy. A series of three patients who received docetaxel in combination with other chemotherapies developed clinically near-identical, distinctive periorbital rashes. Rashes resolved by resolving underlying docetaxel-induced epiphora in conjunction with ophthalmological consultation, topical skin-directed care, and in some cases, chemotherapy dose reduction. It is important for dermatologists and oncologists to recognise the increased severity of cutaneous reactions when docetaxel is used in combination chemotherapy.

Clinical Significance of Myelosuppression Associated with the Use of Dasatinib and Nilotinib As Initial Therapy in Chronic Phase (CP) of Chronic Myeloid Leukemia (CML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2761-2761
Author(s):  
Theresa Liu-Dumlao ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Elias Jabbour ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Clinical Significance ◽  
Research Funding ◽  
Chronic Phase ◽  
Patient Characteristics ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Significant Difference ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2761 Background: Frontline treatment with tyrosine kinase inhibitors (TKIs) has improved prognosis for patients with chronic myelogenous leukemia (CML). Myelosuppression is the most common adverse event (AE) seen during therapy with frontline second generation TKIs, dasatinib and nilotinib. The impact that grade 3/4 myelosuppression has on future outcome has not been described. Aim: To define the patient characteristics and clinical significance of myelosuppression associated with the use of dasatinib or nilotinib as initial therapy for CML. Methods: From August 2005, 204 patients (pts) diagnosed with CML-CP were treated with dasatinib (n=99) or nilotinib (n=105) in parallel trials. Prior imatinib exposure of less than 4 weeks was allowed. Complete blood counts (CBC) and differentials were done weekly in the first month, every 1–2 months up to the first year, every 3–4 months in the second year, and every 4–6 months thereafter. Results: A total of 44 (42%) pts developed grade 3/4 myelosuppression (MS) defined under CTCAE v4.0 criteria as hemoglobin (Hb)<8g/dL (n=5), absolute neutrophil count (ANC)<1×109/L (n=32), and platelet count (Plt)<50×109/L (n=21); 12 (30%) developed more than one cytopenia. MS occurred in 30 pts on dasatinib (anemia 13%, neutropenia 73%, thrombocytopenia 40%), and 14 pts on nilotinib (7%,71%,64%, respectively). Comparing patient characteristics between those who experienced myelosuppression vs. no myelosuppression, there was no significant difference in age, prior imatinib therapy, percent Ph positivity, or baseline hematologic parameters. There was a trend for more pts in the intermediate Sokal risk category among pts with MS. Of the 44 patients with MS, 39 (89%) experienced the event for the first time within 3 months from initiation of therapy. Five (11%) experienced the event after the first 3 months of treatment: 2 eventually came off study (one for resistance and the other for disease progression, both on nilotinib), and 3 (all on dasatinib) continued on therapy, able to achieve CMR. Complications associated with MS included hospitalization in 2 pts (one for pneumonia, and another for flu and prolonged QTc); 6 (14%) required antibiotics; 2 (5%) required blood transfusions; and 2 (5%) required growth factors (erythropoietin). MS led to TKI dose reduction in 9% of all pts treated (41% of those with MS), including 13% of those on dasatinib, and 5% of those on nilotinib. Dose reduction resolved MS in most instances. Recurrence of MS was seen in 10 pts, 2 of whom had progression of disease to blast phase/AML. The outcome of pts with MS is described in table 1 compared to those without MS. Patients with MS had a significantly lower rate of CCyR, MMR, CMR and EFS compared to those without MS. Conclusion: MS is a common AE among pts receiving therapy with dasatinib or nilotinib as initial therapy for CML that frequently leads to dose reductions, and is associated with an inferior outcome. Whether the worse outcome reflects decreased dose intensity, or whether the outcome and decreased tolerance to therapy reflect an intrinsic difference in disease biology remains to be determined. Disclosures: Kantarjian: BMS: Research Funding; Novartis: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Jabbour:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Treatment of Lower Risk MDS with Del 5q with Lenalidomide (LEN): Results of the French ATU Program.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2764-2764 ◽  
Author(s):  
Fabien Le bras ◽  
Marie Sebert ◽  
Charikleia Kelaidi ◽  
Thierry Lamy ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
Side Effects ◽  
Dose Reduction ◽  
Median Time ◽  
Lower Risk ◽  
Research Funding ◽  
Health Agency ◽  
Historical Cohort ◽  
Median Response ◽  
Grade 3

Abstract Abstract 2764 Poster Board II-740 Background: LEN is particularly effective on anemia of lower risk MDS with del 5q (List et al, NEJM, 2006). A compassionate program (ATU) of LEN in low and int 1 risk MDS with del 5q and transfusion dependence was opened by the French health agency between Jan and Sept 2007. Methods: Patients (pts) received 10 mg of LEN/day, 3 weeks on, 1 week off. Response was assessed after 8, 16, 32, and 48 weeks according to IWG 2006 criteria. After the first months of the program, G-CSF use was recommended in case of grade 3-4 neutropenia in order to avoid dose reduction. Results: 95 pts from 35 centers were enrolled. Median age was 73 [42–92], M/F 25/70, median interval from diagnosis to LEN was 29 months (range 1–234). Median follow-up after inclusion was 16 months. At inclusion (WHO classification), 41 pts had del 5q syndrome, 8 RA, 9 RARS, 2 RCMD-RS, 10 RCMD, 1 CMML and 24 RAEB-1. IPSS was low in 29/95 (31%) and int-1 in 66/95 (69%). Del 5q was isolated, with 1 additional and > 1 additional abn in 75/95 (79%), 13/95 (14%), and 6/95 (6%) pts respectively (resp). 62 pts had previously received an erythropoietic stimulating agent (ESA). Median transfusion requirement was 4 units/2 months and platelet count < 100G/L and ANC < 1G/L present in 9.5% and 12.6%, resp. 62/95 pts (65%) achieved erythroid response, including 60 (63%) transfusion independence (TI). Median time to TI was 16 weeks. TI was achieved in 49/75 (65%), 7/13 (54%) and 4/6 (67%) pts with isolated del 5q, del 5q+1abn, del5q + >1abn, resp (p=0.5). Complete, partial and no cytogenetic response were observed in 20%, 40%, 40% pts resp. TI rate was not significantly influenced by concomitant G-CSF (n=25) vs no G-CSF (72% vs 60%, p=0,34), previous ESA vs no ESA (61 vs 73%, p=0.13), interval from diagnosis<2 years vs >2 years (69 vs 59%, p=0.5) or IPSS low vs Int-1 (52% vs 66.7%, p=0.36) but there was a trend for higher TI rate in pts with baseline platelets >100 G/l vs <100 G/l (68.4% vs 33%, p=0.06). Median daily dose of LEN during the first 16 weeks was 7.5 mg (2.5–10). During the first 8 weeks, Grade III-IV neutropenia and thrombocytopenia were seen in 62% and 25% of cases, leading to dose reduction in 55% of the pts. 7 pts had early discontinuation of LEN due to non hematological side effects in 4 (diarrhea, thrombosis and skin reaction), patient decision in 1 and cytopenias in 2 pts. 8 pts developed deep venous thrombosis (DVT) after a median of 16 weeks (range 8–90) of LEN. 7 of them were females, 6 had achieved TI, none of them had experienced thrombocytopenia at week 8 and only 1 grade 3 thrombocytopenia at week 16. In pts who achieved TI and had reached Hb levels >13 g/dl, 5/31 (16%) developed DVT, compared to 1/29 (3%) with maximum Hb level <13 g/dl (p=0.1). 2 pts died from sepsis while having grade 4 neutropenia (in spite of G-CSF in 1 case) and 1 pt, died from CNS bleeding while having grade 4 thrombocytopenia. All 3 pts had pancytopenia at onset of LEN. Non hematological Grade 3-4 side effects were Quincke's oedema (n=1) and rash (n=1). 10 (16%) pts who achieved TI relapsed after a median time of 15 months (10–22). Median response duration was not reached. With a median follow up of 16 months since LEN onset, 6 pts (6.3%) had progressed to AML 7–15 months (median 10) after LEN onset, and 12–149 months (median 25) after diagnosis. In those pts, whose median age was 71 (62–82), 2 had achieved TI, 4 (66%) had RAEB-1, 2 had isolated del 5q, and 4 had del 5q+1 abn), 2 had IPSS low and 4 int-1. At AML progression, 2/3 evaluable pt had persistant del 5q without new abn and 1 had an isolated t(1;3) without 5q deletion, that was already present at onset of LEN. 13 pts died during follow up, including 4 of those who had achieved TI. OS at 16 months was 86%, 95% and 66% in the whole cohort, in pts who achieved TI and in non responders, respectively (p=0.0005). In a historical cohort of 37 lower risk MDS with del 5q treated before the LEN era, and included in GFM trials using ESA, with a median follow-up of 51 months since diagnosis (4–233), 7 pts (19%) had progressed to AML, 12–54 months (median 35) after diagnosis. Conclusion: Our results confirm the high rate of TI achieved with LEN in lower risk MDS with del 5q with acceptable toxicity . Cytopenias should however be closely monitored during the first weeks of treatment, and our results also suggest that achieving Hb level> 13g (especially in females) may increase the risk of DVT. Finally, the rate of AML did not appear to be higher than in lower risk MDS with del 5q treated in the pre LEN era, although continued follow up remains necessary. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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