Treatment with Imatinib in Very Elderly (> 75 Years) CML Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1096-1096
Author(s):  
Roberto Latagli Ata ◽  
Massimo Breccia ◽  
Simona Sica ◽  
Antonio Spadea ◽  
Ada D’Addosio ◽  
...  
Keyword(s):  
Late Toxicity ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
Very Elderly ◽  
Molecular Remission ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3 ◽  
Early Toxicity ◽  
Complete Haematological Response

Abstract Median age of patients with CML is about 65 years, according to SEER 2000–2005 data. However, the treatment with Imatinib in elderly has been seldom specifically addressed: in particular, there is a lack of data regarding very elderly CML patients. To highlight peculiar aspects of toxicity and efficacy of Imatinib in this subset which accounts for at least 10–15% of all CML cases, we revised retrospectively 28 CML patients treated with Imatinib when aged > 75 years from 4 haematological Institution in Rome; there were 12 males and 16 females, median age at Imatinib was 78.7 years (IR 75.8 – 82.9), Sokal Risk at diagnosis was intermediate in 20 patients, high in 6 and not valuable in 2. One or more concomitant diseases requiring specific treatments were present in 26/28 patients (92.8%), with 15 patients (53.5%) assuming 3 or more concomitant drugs. Nine patients (32.1%) have been pretreated ≥ 6 months with HU before starting Imatinib; on the whole, median time from diagnosis to Imatinib was 1.8 months (IR 0.7 – 25.1). Starting dose of Imatinib was 400 mg/day in 23 patients (82.1%) and 300 mg/day in 5 patients (17.9%); overall, 15 patients (53.5%) (14/23 at 400 mg starting dose and 1/5 at 300 mg starting dose) needed a dose reduction and 6 (21.4 %) discontinued Imatinib for toxicity (early toxicity in 4 and late toxicity in 2). Excluding the 4 patients who discontinued Imatinib due to early toxicity, maximum tolerated daily dose during treatment was 400 mg in 8 patients, 300 mg in 13 patients and 200 mg in 3 patients. According to CTC-AE, grade 3 – 4 haematological and extra-haematological toxicities were observed in 7 (25%) and 12 (42.8%) patients, respectively; 2 patients (7.1%) presented a pleural effusion during Imatinib treatment. All patients were fully evaluable for response to Imatinib, with a median treatment period of 30.6 months (IR 15.7 – 49.2); six patients (21.4%) failed any response, (including 4 patients who discontinued Imatinib due to early toxicity) and 22 (78.6%) achieved a complete haematological response (CHR). Among these 22 patients in CHR, 4 refused any other karyotipic or molecular evaluation (3 are still alive in CHR, 1 died in CHR from unrelated cause after 44,5 months) and 17/18 (60.7% of all 28 patients) achieved a cytogenetic response (CyR), major in 1 patient and complete in 16 patients. In addition, 7 patients (25% of all 28 patients) achieved a complete molecular remission, with an undetectable BCR/ABL hybrid gene at qualitative nested PCR. In conclusion, Imatinib at reduced daily dose of 300 mg seems a relatively safe and quite effective treatment for very elderly CML patients; from our data, no upper age limit should be given for TKinhibitors treatment but also very elderly (and with concomitant severe diseases) patients should have this chance of cure.

Imatinib In Very Elderly CML Patients: What Can We Achieve?.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1229-1229
Author(s):  
Roberto Latagliata ◽  
Dario Ferrero ◽  
Francesco Cavazzini ◽  
Malgorzata Monika Trawinska ◽  
Massimo Breccia ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Initial Dosage ◽  
Chronic Phase ◽  
Late Toxicity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Very Elderly ◽  
Starting Dose ◽  
Early Toxicity

Abstract Abstract 1229 In the “real world” of clinical practice, many very elderly CML patients have been treated with imatinib (IM), but there are few data on the results and the best initial dosage in such patients. To highlight peculiar aspects of toxicity and efficacy of IM in this subset which accounts for at least 10–15% of all CML cases, we retrospectively revised 156 CML patients in chronic phase treated with IM when aged > 75 years from 23 haematological Institutions in Italy; there were 85 males and 71 females, median age at IM start was 78.4 years (IR 76.1 – 81.4), Sokal Risk at diagnosis was low in 2 patients, intermediate in 90, high in 50 and not evaluable in 14. One or more concomitant diseases requiring specific treatments were present in 144/156 patients (92.3%), with 94 patients (60.2%) assuming 3 or more concomitant drugs. Thirty patients (19.2%) were in late chronic phase (≥ 12 months from diagnosis) and pretreated (25 with HU and 5 with IFN) before starting IM; on the whole, median time from diagnosis to IM was 1.2 months (IR 0.5 – 3.6). Starting dose of IM was 400 mg/day in 117 patients (75.0%) and 300 mg/day or less in 39 patients (25.0%); overall, 59 patients (37.8%) (52/117 at 400 mg starting dose and 7/39 at 3 300 mg starting dose) needed a dose reduction and 18 (11.5%) discontinued IM for toxicity (early toxicity in 13 and late toxicity in 5). Excluding the 13 patients who discontinued IM due to early toxicity, maximum tolerated daily dose during treatment was 400 mg in 63 patients, 300 mg in 51 patients and < 300 mg in 29 patients. According to CTC-AE, grade 3 – 4 hematological and extra-hematological toxicities were observed in 34 (21.7%) and 34 (21.7%) patients, respectively; 5 patients (3.2%) presented a pleural effusion during IM treatment. After a median treatment period of 29.4 months (IR 7.9 – 54.4), 8 patients (5.1%) are still too early (< 6 months of treatment), 13 (8.3%) discontinued IM due to early toxicity, 3 (1.9%) were resistant and 1 (0.7%) died from unrelated cause early after IM initiation: the remaining 131 patients (84.6%) achieved a complete haematological response (CHR). Among these 131 patients in CHR, 11 refused any other karyotipic or molecular evaluation (1 lost CHR and shifted to hydroxyurea, 4 are still alive in CHR, 6 died in CHR from unrelated causes), 17 achieved CHR only and 103 (66.0% of all 156 patients) achieved a cytogenetic response (CyR), which was major in 11 patients and complete (CCyR) in 92 (58.9% of all 156 patients). In addition, among the 92 patients in CCyR, 62 (39.7% of all 156 patients) achieved a molecular response (major molecular response in 40 patients and complete molecular response with an undetectable BCR/ABL hybrid gene at qualitative nested PCR in 22 patients). After a median follow-up of 34.0 months (IR 12.9 – 60.0), 36 patients have died (5 from disease progression and 31 from unrelated causes), 4 patients were lost to follow-up and 116 are still alive: 2-year and 4-year overall survival were 90.2% (CI95% 84.8 – 95.6) and 76.8% (CI95% 68.6 – 85.0), respectively. In conclusion, results from this large unselected cohort of patients show that should be definitely considered unethical to avoid IM therapy to any elderly patient; no upper age limit should be given but also very elderly (and with concomitant severe diseases) patients should have this chance of cure. The role of a reduced starting dose of IM warrants further studies. Disclosures: No relevant conflicts of interest to declare.

Re-irradiation for intra-thoracic tumours and extra-thoracic breast cancer: dose accumulation, evaluation of efficacy and toxicity based on a literature review

2021 ◽  
Author(s):  
Dorota Gabrys ◽  
Roland Kulik ◽  
Agnieszka Namysł-Kaletka
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Local Control ◽  
Treatment Time ◽  
Late Toxicity ◽  
Breast Conserving Therapy ◽  
Published Data ◽  
Overall Treatment Time ◽  
Grade 3 ◽  
Early Toxicity

The improvement seen in the diagnostic procedures and treatment of thoracic tumours means that patients have an increased chance of longer overall survival. Nevertheless, we can still find those who have had a recurrence or developed a secondary cancer in the previously treated area. These patients require retreatment including re-irradiation. We have reviewed the published data on thoracic re-irradiation which shows that some specific healthy tissues can tolerate a significant dose of irradiation and these patients benefit from aggressive treatment, however, there is a risk of damage to normal tissue under these circumstances. We analysed the literature data on re-irradiation in the areas of vertebral bodies, spinal cord, breast, lung and oesophagus. We evaluated the doses of primary and secondary radiotherapy, the treatment techniques, as well as the local control and median or overall survival in patients treated with re-radiation. The longest OS is reported in the case of re-irradiation after second breast-conserving therapy where the 5 year OS range is 81 to 100% and is shorter in patients with loco-reginal re-irradiation where the 5-y OS range is 18 to 60%. 2 year OS in patients re-irradiated for lung cancer and oesophagus cancer range from 13 to 74% and 18 to 42%, respectively. Majority grade ≥3 toxicity after second breast-conserving therapy was fibrosis up to 35%. For loco-regional breast cancer recurrences, early toxicity occurred in up to 33% of patients resulting in mostly desquamation, while late toxicity was recorded in up to 23% of patients and were mostly ulcerations. Early grade ≥3 lung toxicity developed in up to 39% of patients and up to 20% of Grade five hemoptysis. The most frequently observed early toxicity grade ≥3 in oesophageal cancer was oesophagitis recorded in up to 57% of patients, followed by hematological complications which was recorded in up to 50% of patients. The most common late complications included dysphagia, recorded in up to 16.7% of patients. We have shown that thoracic re-irradiation is feasible and effective in achieving local control in some patients. Re-irradiation should be performed with maximum accuracy and care using the best available treatment methods with a highly conformal, image-guided approach. Due to tremendous technological progress in the field of radiotherapy, we can deliver radiation precisely, shorten the overall treatment time and potentially reduce treatment-related toxicities.

An Open-Label Phase 2 Study of Lenalidomide in Combination with Oral Dexamethasone in the Previously Untreated, Symptomatic Patients with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2895-2895 ◽  
Author(s):  
Christine Chen ◽  
Harminder Paul ◽  
Luisa Del Rizzo ◽  
Lisa W Le ◽  
Ellen Nong Wei ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Abstract 2895 Introduction: Lenalidomide is an immunomodulatory agent with promising anti-tumor activity in CLL. The use of lenalidomide in this disease, however, can be complicated by tumor lysis syndrome (TLS) and frequent tumor flare (TF). From our experience using low-dose lenalidomide (starting dose 2.5mg, titrating to a target of 10mg daily), TLS can be prevented but TF remains frequent (Chen et al. JCO 2010). In addition, when using low-dose single-agent lenalidomide, few complete responses (CR) are achieved. We therefore proposed the combination of lenalidomide and pulse dexamethasone, aiming to enhance anti-tumor activity through both synergy and mitigation of toxicities such as TF, enabling escalation to higher doses of lenalidomide. Our previous observation of “rebound” peripheral lymphocytosis when using intermittent dosing of lenalidomide led to the current use of continuous daily dosing. We present an interim analysis of the initial 18 of 31 planned pts in this ongoing trial of lenalidomide and dexamethasone as first-line CLL therapy. Methods: Eligible pts were previously untreated with symptomatic CLL (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The starting dose for lenalidomide is 5mg daily continuously, with 5mg escalations every 28 days to a maximum of 25 mg, and dexamethasone 12 mg daily orally days 1–7, 14, 21 of each 28 day cycle, both to a maximum of 18 cycles. Supportive measures: allopurinol for TLS prophylaxis, DVT prophylaxis with low dose ASA, sulfatrim for PJP prophyaxis. Results: Demographics: To date, 18 pts have been enrolled: median age 61 yrs (range 40–84), male 13 pts (72%), Rai stage III-IV 13 pts (72%), baseline median Hb 98g/L (range 77–137), absolute lymphocytes 194.5 ×109/L (range 9.3–469.9), ß2M 319 nmol/L (range 253–813; normal <170), bulky nodes 15 pts (83%), organomegaly 9 pts (50%), del17p/del11q on FISH 3 pts (17%), ZAP70+ 12 pts (67%) and unmutated IgVH in 9 of 17 pts tested (53%). Seventeen pts have received at least 1 cycle and are evaluable for toxicity and response. The median number of cycles received is 8 (range 1–18). Hematologic toxicity: 9 pts (53%) have developed Gr 3–4 neutropenia during at least 1 cycle; 4 pts (24%) febrile neutropenia; 6 pts (35%) have required GCSF support. Only 2 pts (12%) have developed Gr 3–4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Non-desquamating rash (65%), fatigue (59%), diarrhea (53%), cough (53%), insomnia (47%), and constipation (47%), are common (most grade 1–2). Grade 3–4 toxicities include: atrial fibrillation with pulmonary embolism (1 pt), fatigue (2 pts), insomnia (1 pt), skin rash (1 pt), diarrhea (1 pt), muscle weakness (1 pt), infection (1 pt). Infections are frequent (all grades in 50% of pts, grade 3 in 6%), primarily affecting upper airway/lungs. One pt developed H1N1 influenzae, complicated by aspergillus pneumonia and multiorgan failure. In contrast to the high rate of TF from our previous single-agent lenalidomide trial (88%), TF is considerably less common in the current trial (5 pts; 29%). No TLS has been noted. Dose modifications/study withdrawals: The maximum 25mg dose has been achieved in 4 pts, with a median tolerated daily dose of 15 mg (range 2.5–25 mg). Grade 3–4 neutropenia is the most common cause of dose interruptions/reductions. Responses: All 17 pts have achieved stable disease (SD) or better with overall responses 59%: 9 PR (53%), 7 SD (41%), 1 CR (6%). Responses were reached at a median of 4 months (range 1.8–9.6). No patients have progressed to date. Correlatives: Recent studies have identified cereblon (CRBN) as a direct target of lenalidomide with expression required for anti-tumor activity. CRBN protein was detected by Western blot analysis in CD19-selected cells derived from screening blood samples of all 17 pts evaluated to date and correlation with response is ongoing. Conclusion: Preliminary results from this phase 2 study suggests that lenalidomide plus dexamethasone has significant activity in previously untreated CLL, is generally well-tolerated, and dramatically reduces the incidence of TF symptoms. This may facilitate dose escalation beyond the 10mg daily dose used in our previous single agent study and lead to higher quality responses. Rebound lymphocytosis has not been noted with continuous dosing. Response data are encouraging but whether this combination can achieve durable CR is forthcoming. Disclosures: Chen: Celgene: Honoraria, Research Funding; Lundbeck: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Johnston:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

A Phase 1/2 Study Of Bosutinib (SKI-606) In Japanese Adults With Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia (CML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2736-2736
Author(s):  
Naoto Takahashi ◽  
Kenichi Ishizawa ◽  
Chiaki Nakaseko ◽  
Yukio Kobayashi ◽  
Kazuteru Ohashi ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Clinical Activity ◽  
Molecular Response ◽  
Multiple Doses ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3

Abstract Background Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor, has demonstrated efficacy and acceptable safety in patients (pts) with chronic phase (CP)-CML resistant/intolerant to imatinib (IM). This ongoing open-label, 2-part, phase 1/2 study evaluated the safety, pharmacokinetics (PK), and efficacy of BOS in Japanese pts with Ph+ CML. Methods In this study, Part 1 was designed to confirm the safety of BOS up to 600 mg/d (or establish a maximum tolerated dose <600 mg/d) and evaluate PK parameters in IM-resistant/intolerant CP-CML pts. In Part 1, BOS (400 mg, 500 mg, and 600 mg) was administered to successive cohorts of pts aged ≥20 to <75 y as a single daily dose on d 1 and as a continuous once-daily dose from d 3, with each cohort (3-6 pts) evaluated for 28 d before enrolling the next dosing cohort. Part 2 evaluated the efficacy and safety of BOS in CP-CML or advanced (ADV) CML pts after resistance/intolerance to IM (second-line [2L]) or to IM plus dasatinib or nilotinib (third-line [3L]; exploratory cohort). In Part 2, BOS (starting dose: 500 mg/d) was administered to pts aged ≥20 y, with dose escalation to 600 mg/d allowed for lack of efficacy. The primary efficacy endpoint was the cumulative major cytogenetic response (MCyR) rate by wk 24 in CP-CML 2L pts (primary cohort). Results In Part 1, 17 pts received BOS (400 mg, n=7, 500 mg, n=7; 600 mg, n=3); 1 pt each in the 400 mg and 500 mg dose groups was not evaluable for dose limiting toxicities (DLTs) due to early study discontinuation (disease progression and pt request, respectively). DLTs during the first 28 d of treatment occurred in 1/6 pt receiving BOS 400 mg (grade 3 liver injury) and 1/6 pt receiving BOS 500 mg (grade 4 abnormal hepatic function); no DLTs occurred in the 3 BOS 600-mg pts. BOS 500 mg was chosen as starting dose for Part 2 based on DLTs and previous results (Cortes et al. Blood. 2011;118:4567-76). PK analyses indicated relatively slow absorption, with a median Tmax of ∼4 h after single or multiple doses of BOS 400–600 mg. BOS exposure (Cmax and AUC) generally increased with increasing dose after single and multiple doses. In Part 2, 46 additional pts were enrolled (2L, n=35 [28 CP-CML, 7 ADV]; 3L, n=11 [10 CP-CML, 1 accelerated-phase (AP)]); 63 pts were treated with BOS (median [range] age: 55 [20-78] y; 62% male; entry diagnosis: CP-CML, n=58; AP-CML, n=3; blast phase [BP]-CML, n=2). Median follow-up was 132 wk for 2L pts and 37 wk for 3L pts. In the CP-CML 2L cohort in Part 2 (n=28), the MCyR rate by wk 24 was 36% (10/28 pts; complete [CCyR], n=8; partial [PCyR], n=2) (primary endpoint); maintained MCyR at wk 24 was 64% (18/28 pts; CCyR, n=16; PCyR, n=2); median time to MCyR was 12.3 wk. Only 1 of 13 CP-CML 2L pts who attained MCyR at any point during the study lost it. Cumulative major molecular response (MMR) rate through the study was 43% (12/28 pts). AP/BP transformation occurred in 1 CP-CML 2L pt; at wks 48 and 96, progression-free survival (PFS) rates were 100% and 94%, respectively, and overall survival (OS) rate was 96% (both). Of 7 ADV 2L pts, 1 had confirmed complete hematologic response (cCHR) at wk 84 with duration of 95 wk (cCHR lost). AP/BP transformation occurred in 1 ADV 2L pt; at wks 48 and 96, PFS rate was 21% (both), and OS rate was 43% (both). In the 3L cohort, the cumulative MCyR rate by wk 24 and maintained MCyR rate at wk 24 were 18% (2/11 pts) and 64% (7/11 pts [CCyR, n=6; PCyR, n=1]); cumulative MMR rate through the study was 18% (2/11 pts). The only 3L pt with AP-CML attained cCHR at 12 wk with a duration of 24 wk as of the date of this analysis (censored due to data cutoff). No AP/BP transformation occurred in the 3L cohort; treatment duration was inadequate for assessment of PFS and OS. Overall, the most common treatment-emergent AEs (TEAEs) were diarrhea (95%), rash (57%), nasopharyngitis (51%), nausea (38%), vomiting (38%), increased alanine aminotransferase (ALT; 38%), lymphopenia (35%), thrombocytopenia (30%), and increased aspartate aminotransferase (30%). Grade 3/4 TEAEs were reported in 54 (86%) pts, most commonly lymphopenia (21%), increased lipase (19%), neutropenia (18%), thrombocytopenia (18%), and increased ALT (18%). 16 (25%) pts discontinued treatment due to AEs. No deaths occurred within 30 d of last BOS dose. Conclusions The safety and PK profiles of BOS up to 600 mg/d was confirmed in Japanese pts with Ph+ CML resistant/intolerant to IM. BOS 500 mg/d demonstrated clinical activity and an acceptable safety profile in this population. Disclosures: Kobayashi: Ariad: Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Research Funding; Ohtsuka: Research Funding; Onconova: Research Funding. Shibata:Pfizer Japan Inc: Employment. Fujii:Pfizer Japan Inc: Employment. Ono:Pfizer Japan Inc: Employment.

Long Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome without Del 5q Cytogenetic Abnormalities.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 250-250 ◽  
Author(s):  
Azra Raza ◽  
James E. Reeves ◽  
Eric J. Feldman ◽  
H. Joachim Deeg ◽  
Luke Dreisbach ◽  
...  
Keyword(s):  
Risk Groups ◽  
Cytogenetic Response ◽  
Red Blood Cell Transfusion ◽  
Hematopoietic Stem ◽  
Vein Thrombosis ◽  
Transfusion Independence ◽  
Starting Dose ◽  
Grade 3 ◽  
Atypical Cml ◽  
Deep Vein

Abstract Background: MDSs are clonal hematopoietic stem cell malignancies characterized by cytopenias resulting from ineffective hematopoiesis. A phase 2 study of lenalidomide (MDS-002) demonstrated hematological improvement in patients with MDS without an associated deletion 5q cytogenetic abnormality (List AF, et al. Haematologica2006;91[suppl1]:379[abst 1032]). We now report multicenter results after 〉2 yrs follow-up. Methods: A total of 214 pts with transfusion-dependent anemia were categorized into the following IPSS MDS risk groups after central review of bone marrow morphology, karyotype, and peripheral blood findings: Low/Int-1 (168 [78%]); Int-2/High (8 [4%]); and unclassified (38 [18%]). Patients were unclassified for missing or inadequate marrow studies for central review (morphology [29] or cytogenetic [7]) or other diagnoses (AML [1], atypical CML [1]). Patients were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI) (IWG criteria), hemoglobin (Hgb) response, and safety. The starting dose of lenalidomide was 10 mg (daily or daily × 3 wks q28d cycle). Results: Overall, 56 (26%) of 214 enrolled patients achieved RBC-TI. Median time to RBC-TI was 5 wks, median duration of RBC-TI response was 41.0 wks (range, 8.0–136.4), and median Hgb increase achieved during RBC-TI was 3.2 g/dL (range, 1.0–9.8). An additional 36 patients experienced a ≥ 50% reduction in RBC transfusions (overall hematological improvement in 92 [43%] patients). Overall, 47 (22%) patients had an abnormal karyotype at baseline and 9 (19%) patients achieved a cytogenetic response (4 complete). The most common drug-related grade 3/4 adverse events (AEs) were neutropenia and thrombocytopenia (25% and 20%, respectively). Deep vein thrombosis occurred in only 2 (1%) patients. The duration of RBC-TI was ≥ 52 weeks in 21 (38%) patients. Among these 21 patients, 14 (67%) did not require a lenalidomide dose reduction during the first 52 weeks of treatment. Analyses of response variables will be presented. Dose-limiting neutropenia/thrombocytopenia was not reported after 52 weeks. The most commonly reported AEs after 52 weeks were mild-moderate diarrhea and fatigue (38% and 29%, respectively). Conclusion: Lenalidomide is an active, well-tolerated treatment in MDS patients with transfusion-dependent anemia that is not associated with a deletion 5q abnormality. The rate of erythroid hematologic improvement and duration of RBC-TI is encouraging and offers a possible alternative to cytokine therapy.

Dasatinib in the Treatment of CML Patients Aged > 60 Years Resistant/Intolerant to Imatinib

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4253-4253
Author(s):  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Fabio Stagno ◽  
Silvia De Matteis ◽  
Mario Annunziata ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Chronic Phase ◽  
Elderly Subjects ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Starting Dose ◽  
Median Period ◽  
Grade 3

Abstract Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in elderly patients. To highlight this issue, 37 patients treated with Dasatinib when aged &gt; 60 years were retrospectively evaluated. There were 21 males and 16 females, median age at Dasatinb was 69.3 years (IR 64.9–73.0), Sokal Risk at diagnosis was low in 13 patients, intermediate in 14, high in 5 and not valuable in 5. Twenty-two patients (59.4%) were primary resistant, 4 (10.8%) intolerant and 11 (29.8%) secondary resistant to Imatinib; all but 2 patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 99.2 months (IR 56.8–124.5); 25/37 patients (67.5%) have been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 20/37 (54%) by Imatinib at increased dose (600–800 mg/day) with an overall median period of Imatinib treatment of 52.8 months (IR 26.2–60.9). In addition, 7/37 patients (18.9%) received other 2nd line treatment (3 with Nilotinib, 2 with Imatinib + HU and 2 with other drugs) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 18 patients and 100 mg/day in 19 patients, respectively. After a median period of treatment of 9.4 months (IR 3.0–19.1) all patients were evaluable for toxicity; among 18 patients receiving 140 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 14 (77.7%) and 6 (33.3%) patients, respectively; among 19 patients receiving 100 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 4 (21.0%) and 1 (5.2%) patients, respectively. Pleuro-pericardial effusions occurred in 3 patients, all treated with 140 mg as starting dose. Overall, 3/37 patients (all treated with 140 mg) discontinued permanently Dasatinib due to early toxicity; a dose reduction was needed in 17/37 patients [16/18 (88.8%) treated with 140 mg and 1/19 (5.2%) with 100 mg]. As to response, 28 patients were considered evaluable (≥ 6 months of treatment) and 9 considered as too early; five patients (17.9%) did not have any response (including 3 patients with early Dasatinib discontinuation for toxicity) and 23 (82.1%) achieved Complete Haematological Response (CHR). Furthermore, 11/28 patients (39.2%) achieved a Cytogenetic Response (CyR) (Major CyR in 4 and Complete CyR in 7) and 4/28 patients (14.2%) achieved a molecular response. In conclusion, Dasatinib, when employed at the current recommended starting dose of 100 mg/day; seems effective and very well tolerated also in heavily pretreated elderly subjects; these results are encouraging also for a future use of this drug in early chronic phase elderly patients.

CONKO-008: Oxaliplatin (O)/folinic acid (FA)/5-fluorouracil (5-FU) (24h) in combination with lapatinib as second-line therapy in pancreatic cancer after gemcitabine failure: A phase I trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14533-e14533
Author(s):  
Jens Stieler ◽  
Uwe Pelzer ◽  
Marianne Sinn ◽  
Jana Kaethe Striefler ◽  
Bernd Dörken ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tyrosine Kinase ◽  
Folinic Acid ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Phase Ii Trials ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3 ◽  
Dose Limiting Toxicity

e14533 Background: ErbB-1 and ErbB-2 as its enhancer are expressed in pancreatic cancer. Based on the results of the 2nd-line chemotherapy (CT) with Oxaliplatin, 5-FU and Folinic acid (OFF) (CONKO-003; ASCO 2008) and the activity of EGFR- tyrosine kinase inhibition in pancreatic cancer (Moore JCO 2007), this trial aims to further improve therapeutic options for patients after Gemcitabine failure by combining OFF with lapatinib, a combined ErbB-1 and ErbB-2 tyrosine kinase inhibitor which showed preclinical synergy with 5-FU (Kim PloS One 2009). Methods: The daily dose of lapatinib combined with oxaliplatin 85 mg/m2 (2-4 h infusion d 8, 22), 5-FU 2000 mg/m2 (24 h continuous infusion d1,8,15,22 q d 42) and FA 200 mg/m2 (30 min infusion d1,8,15,22 q d 42). was expected to be between 750 to 1,500 mg, further dose intensification was not planned. Starting dose for lapatinib was set on 1,000 mg/day, with a minimum of 3 pts. on each level and extension to 6 pts. in case of a dose limiting toxicity (DLT). Maximum tolerated dose (MTD) was defined as a dose level (DL) below the level where 2/6 patients would show DLTs during cycle 1. Results: 18 Pts (12m/6w). have been enrolled in the trial.7 pts. were treated on 1,000 mg/d (DL 1), 5 pts. on level 1,250 mg/d (DL 2), and 6 pts. on 1,500 mg (DL 3). DLTs were met on DL 3 with diarrhea CTC grade 4 and concomitant neutropene enterocolitis in one patient and diarrhea CTC grade 3 in another patient. MTD is thus limited to 1,250 mg lapatinib in combination with OFF. Conclusions: With diarrhea as most prominent cumulative toxicity of the regimen, the maximum dose of lapatinib in combination with OFF is 1,250 mg. This dose may find further use in future phase II trials.

scholarly journals Nilotinib As Second-Line Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase: Thailand Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5448-5448 ◽  
Author(s):  
Kanchana Chansung ◽  
Chittima Sirijerachai ◽  
Arnuparp Lekhakula ◽  
Pongtep Viboonjuntra ◽  
Pimjai Niparuck ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
Second Line ◽  
Serum Lipase ◽  
Failure Group ◽  
Best Response ◽  
T315i Mutation ◽  
Grade 3

Abstract Background: Nilotinib, a second generation tyrosine kinase inhibitor, was proved to have high efficacy on treatment of Philadelphia chromosome positive CML patients who failed or were intolerant to imatinib. Limited data was available on its efficacy and safety in Asian population. Methods: Chronic phase CML patients who have failure, suboptimal response or intolerance to imatinib according to ELN 2009 guideline were treated with nilotinib 400 mg twice daily on 7 centers in Thailand. Prospective data collection for 24 months was performed. Results: There were 106 cases participated in this study, 2 cases with initial T315I mutation were excluded from the study, total 104 cases were analysed. The median age was 46 (16-79) years with a slight male predominance over female at the ratio of 1.4:1 respectively. Twenty five percent received imatinib less than 12 months whilst 20% received imatinib longer than 60 months. The median duration of the prior imatinib treatment was 18 months (2-142 months). Best response to imatinib treatment were major molecular response (MMR) 5.8%, complete cytogenetic response (CCyR) 26%, major cytogenetic response (MCyR) 12.5%, complete hematologic response (CHR) 47%, and no CHR 8.7%. The reasons for nilotinib switching were imatinib failure 65%, imatinib intolerance 28%, imatinib suboptimal response 7%. Sixty-eight percent were completed 24 months follow up. Of those, 32% early discontinued treatment mostly because of unsatisfactory results or adverse events. Two patients died of infection and CNS bleeding during the study period. Evaluation were made every 3 months based on ELN 2009 criteria . Best response to nilotinib treatment included MMR 57%, CCyR 16%, MCyR 6%, CHR 16%, and no CHR 5%. At 3 months, 91%, 35%, and 14% of the patients CHR,CCyR, and MMR, respectively. Achieving CCyR or MMR at 3 months predicted a chance of achieving MMR (P= 0.00001) Those who did not achieve at least CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR and 100% of those achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had significantly better outcome as compared to imatinib failure and imatinib intolerance group (P = 0.017). All of suboptimal response cases achieved CCyR , 86% achieved MMR, no early discontinue treatment in this group. While 75% of failure group achieved CCyR, 62% achieved MMR and 62% of intolerance group achieved CCyR, 38% achieved MMR. The reason for poorer response of intolerance group was high rate of early discontinue due to side effects, 17% vs 5% in the imatinib failure group. Initial BCR-ABL mutation analysis was performed on 90 cases, mutations were found on 16 cases, 2 of them were T315I which were excluded from the study. The cases with mutation significantly had poorer response to treatment than those without mutation (P = 0.001). There was one case with initial G250E mutation, who developed T315I mutation after treatment with nilotinib. At 24 months, 1 case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year progression-free survival and 2-year overall survival was 96% and 98%, respectively. Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events found in 18%, 13%, and 6% of the patients, respectively; however, most of them were grade 1-2, except for 4 cases with grade 3-4 infections .Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%), and leucopenia (4%); and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild. Grade 3-4 events found were hypophosphatemia (6%), hyperglycemia (4%), and elevated serum lipase (4%). Only 10 cases (9%) permanently discontinued nilotinib due to its adverse effects. Conclusions: Nilotinib, as a second line treatment for Thai patients with chronic phase CML showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. Author contact: KanchanaChansung M.D. Division of Hematology, Department of Medicine, Faculty of Medicine, Khonkaen University, Khonkaen, Thailand e-mail: [email protected] Disclosures No relevant conflicts of interest to declare.

scholarly journals The Risk of Relapse in CML Patients Who Discontinued imatinib Can Be Predicted Based on Patients Age and the Results of dPCR Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 813-813 ◽  
Author(s):  
Silvia Mori ◽  
Elisabetta Vagge ◽  
Philipp le Coutre ◽  
Elisabetta Abruzzese ◽  
Bruno Martino ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Median Time ◽  
Median Duration ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Risk Of Relapse

Abstract Introduction. Chronic myeloid leukemia (CML) patients (pts) treated with imatinib first line achieve complete cytogenetic response (CCyR) in > 70% of cases and major molecular response (MMR) in 18-58%. These pts have a life expectancy similar to the general population. However even undetectable BCR-ABL may not equate to eradication of the disease because of the sensitivity of Q-RT-PCR. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, has been recently developed (Goh HG et al., 2011). dPCR corresponds to a 100 fold increase in sensitivity as compared to Q-RT-PCR. Therefore, dPCR by assessing the presence of minimal residual disease with higher sensitivity, could potentially identify pts in whom CML has been eradicated. Aims. The Imatinib Suspension And Validation (ISAV) study is aimed at validating the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results. Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible for this study. Patients had to be in CMR for at least 18 months (mts), with a minimum of 3 Q-RT-PCR performed at their own sites. After signing the informed consent, blood samples are obtained for dPCR and the pts discontinue imatinib therapy. Standard Q-RT-PCR is performed monthly (mts 1-6) and then bimonthly for 36 mts to assess the maintenance of the molecular remission. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resume imatinib treatment at the same dosage used before interruption. Patients’ quality of life during imatinib discontinuation/resumption is evaluated through the EORTC – C30 Quality of Life questionnaire. Results. The enrolment in ISAV began in November 2011 and ended in July 2013. The study enrolled 112 pts: Italy 69.6%, Germany 21.4%, Canada 5.3%, Spain 2.6% and Israel 0.9%. Among the 112 pts, 59.3% were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.8 mts before imatinib discontinuation. To date, the median follow-up (FUP) time is 16.6 mts [95% CI: 14.9-18.2]. Forty-seven pts (43.5%, 95% CI: 34.0-53.4) of the 108 eligible pts relapsed and resumed imatinib; 38/47 (80.9%) of them relapsed in the first 9 mts and the last relapse occurred 19.6 mts after imatinib discontinuation. A loss of CCyR occurred in 11 pts (23.4%): 10/11 CCyR losses were recovered; 1 patient withdrew the consent shortly after obtaining a partial cytogenetic response. No case of CML progression was observed. After the resumption of imatinib the median time to either MMR or CMR was 1.9 [95% CI: 1.2-2.4] mts. Of the 61 not-relapsed pts, 43 (39.8% of the total) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity was 3.6 mts [95% CI: 3.0-4.8] and the range of duration of Q-RT-PCR positivity (below 0.1%) was between 5.7 and 29.2 mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR or duration of CMR was identified. An inverse relationship between pts age and risk of relapse is evident: 90% of pts < 45 years relapsed vs 37.5% in the class ≥ 45 - < 65 years and 27.5% of pts ≥ 65 years, p(χ2)<0.0001. dPCR results showed that 23.4% of pts were positive and 76.6% negative, with a dPCR Negative Predictive Value (NPV) of 63.4% (Tab.1) and a significant NPV ratio (dPCR/Q-RT-PCR) of 1.131 [95% CI: 1.032-1.239]. Age and dPCR results predicted the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥ 45 years and with negative dPCR (30.6%; Fig.1). Conclusions. After 32 mts from the beginning of the study, with a median FUP of 16.6 mts, 43.5% of pts relapsed; the majority of relapses developed in the first 9 months after imatinib discontinuation. Age < 45 years and dPCR positivity are significantly associated with relapses. Funded by Regione Lombardia. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Primary results of the phase 4 BYOND study of bosutinib (BOS) for pretreated chronic phase (CP) chronic myeloid leukemia (CML).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7012-7012 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Camille N. Abboud ◽  
Bjorn T. Gjertsen ◽  
Tim H. Brümmendorf ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Prior Therapy ◽  
Starting Dose ◽  
Insufficient Response ◽  
Grade 3

7012 Background: The tyrosine kinase inhibitor (TKI) BOS is approved for patients (pts) with Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed pts in CP. Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior TKIs. Primary endpoint (not powered) in Ph+ CP CML cohorts is cumulative confirmed major cytogenetic response (MCyR) by 1 y. Results: Of 163 pts who received BOS, 156 had Ph+ CP CML (46, 61 and 49 after 1, 2 and 3 prior TKIs, respectively). Across Ph+ CP CML cohorts, 51.9% of pts were male; median age was 61 y. As of 1 y after last enrolled pt (median follow-up 30.4 mo), 56.4% remained on BOS. Median BOS duration was 23.7 mo and median dose intensity after adjustment due to adverse events (AEs) 313 mg/d. Of 144 evaluable pts with a valid baseline assessment, cumulative confirmed MCyR by 1 y was 71.5% (95% confidence interval [CI] 63.4–78.7). Cumulative complete cytogenetic response rate anytime on treatment was 81.3% (95% CI 73.9–87.3). Cumulative molecular response (MR) rates were high across lines of therapy (Table). 10 deaths occurred (5 on treatment); 1-y overall survival rate was 98.0%. No pt progressed to accelerated/blast phase on treatment. 25.0% discontinued BOS due to AEs and 5.1% due to insufficient response. Most common treatment-emergent AEs (TEAEs) were diarrhea (87.8%) and nausea (41.0%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.7%) and increased alanine aminotransferase (ALT; 14.7%). The only TEAE leading to discontinuation in > 5% of pts was increased ALT (5.1%). Conclusions: Most pretreated pts with Ph+ CP CML had MCyR by 1 y with BOS; a substantial proportion achieved or preserved major MR (MMR) and deep MR in all therapy lines. Results further support BOS use for Ph+ CP CML resistant/intolerant to prior TKIs. Clinical trial information: NCT02228382. [Table: see text]

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