AZA In the Treatment of Therapy Related MDS and AML (tMDS/AML): a Report on 60 Patients by the Groupe Francophone Des Syndromes Myelodysplasiques (GFM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2911-2911
Author(s):  
Jehane Fadlallah ◽  
Cecile Bally ◽  
Bruno Quesnel ◽  
Norbert Vey ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
Response Rate ◽  
De Novo ◽  
Early Death ◽  
Poor Response ◽  
Female Gender ◽  
Median Number ◽  
Hematological Toxicity ◽  
Similar Response ◽  
Best Response ◽  
Wbc Count

Abstract Abstract 2911 Background: AZA gives 50–60% responses and improves OS in higher-risk MDS but its role in t MDS/AML, characterized by a high frequency of unfavorable karyotypes and poor response to available treatments, remains unknown. Methods: An AZA compassionate program (ATU) was opened in France between Dec 2004 and Jan 2009 for higher risk MDS, and for AML not candidates to or refractory to intensive chemotherapy (IC). We analyzed t MDS/AML included in this program and having received at least 1 cycle of AZA, excluding patients (pts) previously treated with chemotherapy (CT) for their tMDS/AML. Results: 60 tMDS/AML were included: M/F:24/36, median age 69 (range 20–87). Primary disease was Breast Carcinoma (n=17), CLL (n=6), Hodgkin's disease (n=4), NHL (n=7), ALL (n=2), ovarian (n=2), liver(n=2), prostate carcinoma (n=2), other cancers (n=16), immunosuppressive therapy for lupus or Lung transplant in the last 2 pts. Treatment of primary neoplasm consisted in C×T in 86% and R×T in 61%. Diagnosis (WHO) was RCMD+/− RS in 4 pts, RAEB-1 in 10 pts, RAEB-2 in 28 pts MDS with myelofibrosis in 1 pt, and AML in 17 pts (including 12 FAB RAEBt). IPSS cytogenetics were fav in 4 (6.7%), int in 11 (18.3%), and unfav in 45 (75%, including 71% Complex karyotypes). Patients received a median of 4 cycles (range 1–24) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d ×7d/4 week) in 73% patients and a less intensive schedule (5d/4w, or <75mg/m2/d) in 27% patients. 25 (41.6%) pts received < 4 cycles, mainly due to early death (32%), failure (28%) or hematological toxicity (16%). Best response according to IWG 2006 criteria was CR in 9 pts (15%), marrow CR (mCR) in 8 (13%), PR in 1, stable disease (SD) with HI in 5 (8%) ie an overall response rate (ORR) of 38%. In pts who received >4 cycles, ORR was 21/35 (60%). Age, WBC count, baseline platelet count, % marrow blasts, karyotype (whatever the categorization) and ECOG status had no impact on ORR. 1, 2 and 3 year survival was 35%, 15% and 7%. Female gender (p=0.02), achievement of response (p=0.003) and ECOG status (0-1 vs 2–4) (p=0.04) had significant impact on OS while karyotype and % marrow blasts had no impact. However, there was a trend for lower OS in patients with chrom 5 abn (2y 0S 7.7% vs 23 %, p=0.08). 9 (15%) patients, all females, median age 55 (range 35–66) were allografted after a median number of 6 AZA cycles (range 2–17), including 3 pts, 4 pts and 2 pts who had achieved CR, mCR and no response to AZA, respectively. 4 (44%) of them were alive after 5+,17+,32+ and 42+ months. By comparison to the 232 pts with de novo MDS/AML included in the same program, tMDS/AML had a higher frequency of complex karyotype (71 vs 29.5, p<0.01), received fewer cycles of AZA (4 vs 6, p=0.0014) due to more frequent discontinuation of AZA before 4 cycles (41.6% vs 25%, p=0.025) mainly related to a higher incidence of early deaths. tMDS/AML had a similar response rate (38% vs 45% in de novo MDS/AML, p=0.67), but significantly shorter OS (2yOS 15% vs 33.3, p=0.003, figure 1). Conclusion: In this cohort of tMDS/AML, survival with AZA was shorter than in de novo MDS/AML, probably largely due to their more severe baseline characteristics. Only 15% of tMDS/AML could be allografted, half of them with so far a favorable outcome. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

A Phase I-II Study of the Efficacy and Safety of Lenalidomide (LEN) Combined to Azacitidine (AZA) in Higher Risk MDS and AML with Del 5q - a Study By the Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2892-2892 ◽  
Author(s):  
Lionel Ades ◽  
Christian Récher ◽  
Julie Lejeune ◽  
Aspasia Stamatoullas ◽  
Marie Sebert ◽  
...  
Keyword(s):  
Phase I ◽  
Primary Endpoint ◽  
Research Funding ◽  
Response Rate ◽  
Early Death ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Median Number ◽  
Intensive Chemotherapy ◽  
Best Response

Abstract Background: Higher risk MDS and AML with del(5q) carry very poor prognosis, but show some response to AZA and LEN as single agents (Adès Blood 2009, Itzykson, Blood 2010). The combination of LEN and AZA has been tested in non-del 5q MDS patients with encouraging results and limited toxicity (Sekeres, Blood 2012). Sequential combination of AZA and LEN has also shown to be feasible and potentially effective in 20 patients with higher-risk MDS with del(5q) in a phase I study (Platzbecker, Leukemia 2013). In this phase I-II trial, we combined escalating doses of LEN to AZA in higher risk MDS and AML with del(5q). Methods: Patients with IPSS int-2 or high MDS, CMML with WBC < 13,000/mm3 and marrow blasts > 10% and AML (20-30% marrow blasts) with 5q deletion with or without additional cytogenetic abnormalities could be included provided they had not previously received LEN or AZA. Patients should also have contra indication to intensive chemotherapy (IC), precluding inclusion in a GFM competing trial combining IC and LEN in higher risk MDS and AML with del 5q. In the present trial, patients received AZA (75 mg/m2 x5 d, every 28 days) combined with escalating doses of LEN (5 mg/d x14 d in cohort 1, 5 mg/d x21 d in cohort 2 and 10 mg/d x21 d in cohort 3). For patients in hematological CR, PR, HI or marrow CR (MDS) and CR or PR (AML) after cycle 2 or 4, treatment was to be continued at the same schedule unless unacceptable toxicity or overt progression occurred. The primary endpoint was response assessed according to IWG 2006 criteria. Secondary endpoints were best response over the 4 cycles and survival. Medians [IQR] are reported unless specified. Intent-to-treat analyses were made. Results: 49 patients were enrolled, including 15, 10 and 24 patients in cohort 1 (LEN 5 mg/d x14d), 2 (LEN 5 mg/d x21d) and 3 (LEN 10 mg/d x21d). 24 were males and the median age was 69 (63-74). According to WHO classification, 1 patient had CMML, 9 RAEB1, 22 RAEB2 and 17 AML. PS was 0, 1 and 2, in 30.8%, 43.6% and 25.6% patients, respectively. However, as said above, patients included in this trial were considered unfit for IC due to their age and/or comorbidities (cardiovascular in 30 patients, pulmonary e in 10, and neurological in 6 pts). Del(5q) was isolated in only 8.3% pts, while 85.4% had del (5q) and at least 2 additional abnormalities (i.e., complex).. IPSS was int-2 in 33% patients and high in 66% patients. Overall, 143 cycles were administered (median 2/patient, including 9 patients who received 6 or more cycles). In the three cohorts, the median number of cycles received was 2 (1-2), 2 (1-4.75) and 4 (2-5.5) respectively. Fifteen (30.6%) patients discontinued treatment before the second cycle, due to early death (n=9), adverse events (n=3), progression (n=2), or CNS hemorrhage (n=1). They were all considered as non responders (primary endpoint). After 2 cycles, 4 (8.2%) achieved CR, 4 (8.2%) marrow CR and 4 (8.2%) stable disease with hematological improvement (ORR= 24%). The best response rate over the 4 courses was 2/15 (13.3%) in cohort 1, 1/10 (10%) in cohort 2, and 9/24 (37.5%) in cohort 3 (ORR=24%). The response rate was 37.5% in patients receiving 10 mg/d, versus 12% in those receiving 5 mg (p=0.051) while other baseline parameters had no impact on response: IPSS (p=0.073), marrow blasts >10% (p=0.16), sex (p=0.74), cytogenetic complexity (p=0.26) or PS (p=0.419). 2/6 CR patients achieved cytogenetic complete response: 0/2 in cohort 1, 0/0 in cohort 2, and 2/4 in cohort 3. One year OS was estimated at 22.9% [95% IC: 12.3-42.5]. We failed to identified any prognostic factor associated with OS (IPSS (p=0.52), marrow blasts >10% (p=0.28), sex (p=0.99), isolated del(5q) (p=0.68), cohort (p=0.2) and PS (p=0.33)). Regarding toxicity, 58 SAEs (grade 3-4) were reported in 38 patients, including 35 infectious events, 7 bleding events, 3 deep venous thrombosis. Conclusion: In this elderly population of higher risk MDS or AML considered unfit for intensive chemotherapy, and with del 5q that was part of a complex karyotype in almost all cases, the combination of AZA with escalated doses of LEN was associated with early discontinuation (<4 cycles) in 30/49 (61.2%) of the patients, mostly due to progression or toxicity, and only 12/49 (24.5%) response. The fact that some responders also achieved cytogenetic response may however be encouraging. Disclosures Vey: Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria. Park:Hospira: Research Funding; Celgene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Clinical Results in Patients with Primary and Secondary Myelofibrosis Treated with Monthly Cycles of Oral Melphalan.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4985-4985
Author(s):  
Ida Carmosino ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Laura Cannella ◽  
Federico Vozella ◽  
...  
Keyword(s):  
Response Rate ◽  
Conflicts Of Interest ◽  
Previous History ◽  
Clinical Results ◽  
Median Number ◽  
Hematological Toxicity ◽  
Costal Margin ◽  
Best Response ◽  
Number Of Treatment ◽  
Spleen Enlargement

Abstract Abstract 4985 Prolonged continuous oral Melphalan treatment was successfully employed in patients with Idiopathic Myelofibrosis (IM); however, a high incidence of evolution into blastic phase (BP) was observed. In order to reduce the incidence of BP and other side effects, a different Melphalan schedule with intermittent monthly cycles was tested at our Institution. From 1/2003 to 2/2009, 24 patients (16 males and 8 females, median age 66.2 years, range 41.7 – 76.2) were enrolled into the study; 19/24 had primary IM while in 5 there was a previous history of Polycythemia Vera/Essential Thrombocythemia. Six patients (25%) had been pretreated with Hydroxyurea. A symptomatic splenomegaly was present in all patients, with median spleen enlargement below costal margin of 12 cm (range 7 – 22). Median WBC level was 11.6 × 109/l (range 3.6 – 63.6), with 11/24 patients having WBC > 12.0 × 109/l; in addition, 3 patients had PLT level > 500 × 109/l, 11 patients Hb level < 10 g/dl and 3 patients had transfusional requirement. Melphalan was administered orally at the dose of 8 mg/day for 5 consecutive days every month. Twelve patients (50%) had a reduction of spleen enlargement > 75%, 2 patients > 50% and 1 patient > 25%, with a global response rate of 15/24 patients (62.5%): the remaining 9 patients had no variation in spleen volume. Elevated WBC values reduced to normal in all but one patient, elevated PLT values reduced to normal in 2 out of 3 patients, transfusional requirement disappeared in 1 out of 3 patients. Median number of cycles to best response was 10 (range 2 – 30). As concerns hematological toxicity, 4 patients had Hb decrease < 8 g/dl, with 3/4 requiring transient transfusional support, and 1 patient had PLT decrease to < 50 × 109/l. One patient resistant to treatment died from broncopneumonia and 1 patient with normal PLT values died from cerebral hemorrhage; two patients had a grade 3 – 4 gastro-intestinal hemorrhage. Interestingly, only 2/24 patients (8.3%) had a BP evolution after 8 and 16 months from start of Melphalan, respectively. After a median number of treatment cycles of 18 (range 2 – 68), 12 patients are still in therapy and 12 discontinued Melphalan due to toxicity (4), resistance (3), relapse (3) or evolution to BP (2). In conclusion, the intermittent cyclic schedule of oral Melphalan seems capable to maintain a good response rate with reduction of symptomatic spleen enlargement in more than 50% of patients without excessive toxicity and with a lower rate of BP evolution, as compared to continuous Melphalan administration. Disclosures No relevant conflicts of interest to declare.

Phase II Study of Clofarabine and Cytosine Arabinoside in Adult Patients with Relapsed AML and in Elderly Patients with Untreated AML Who Are at High Risk of Anthracycline Toxicity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1951-1951 ◽  
Author(s):  
Edward Agura ◽  
R. Brian Berryman ◽  
Laura Brougher ◽  
Barry Cooper ◽  
Andrew De Leon ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Phase Ii ◽  
Response Rate ◽  
De Novo ◽  
High Risk Patient ◽  
Early Death ◽  
Poor Response ◽  
Adult Patients ◽  
Open Label

Abstract PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in adult patients with refractory or relapsed acute myeloid leukemia and in selected elderly patients with untreated AML and heart disease. PATIENTS AND METHODS: In a phase II, open-label trial, 23 patients with de-novo AML, AML evolved from MDS or relapsed AML received a 5 day regimen consisting of clofarabine 40 mg/m2 intravenously over 1 hour followed within 4 hours by Ara-C 1000 mg/m2. The median age was 68 years (range 39–79 years). Fifteen (65%) had received at least one prior cytotoxic regimen (excluding 5-AZA). Significant cardiovascular disease (history of myocardial infarction, bypass grafting, cardiomyopathy) was present in 52% (12/23) prior to therapy. RESULTS: 22/23 received at least one cycle of therapy and 5 received 2 cycles. One early death was due to disease progression. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 20 patients are evaluable for response. The histologic response rate (defined as marrow blasts <5%) is 60% (12/20) consisting of 10 (50%) complete remissions and 2 (10%) partial responses. Complete cytogenetic remissions occurred in 9 patients. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation. CONCLUSION: Clofarabine (40mg/m2) and Ara-C (1000mg/m2) x 5 days is an active and well tolerated regimen in myeloid malignancies including “elderly AML”—a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are being explored for use in allogeneic transplant regimens and with other high-risk patient groups.

P14.13 Severe hematological toxicity during chemoradiation for glioblastoma: Identification of clinical and pharmacological risk factors and consequences for the individual patient

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii40-ii40
Author(s):  
N Grun ◽  
C A den Otter ◽  
M Sintemaartensdijk ◽  
J Osinga ◽  
F E L van den Elzen ◽  
...  
Keyword(s):  
Risk Factors ◽  
De Novo ◽  
Tumour Progression ◽  
Haematological Toxicity ◽  
Female Gender ◽  
Hematological Toxicity ◽  
Severe Toxicity ◽  
Cell Counts ◽  
Adjuvant Temozolomide ◽  
Hospital Visits

Abstract BACKGROUND Besides early tumour progression, standard first-line radiation with concurrent and adjuvant temozolomide in de novo glioblastoma patients is abrogated frequently by severe haematological toxicity. This leads to treatment delays with unknown effect on efficacy and to more hospital visits with increased disease burden. In the present study, we identified clinical and pharmacological risk factors for temozolomide induced severe hematological toxicity. Furthermore, we describe the burden of toxicity for patients and evaluate the effect of severe toxicity on prognosis. METHODS A retrospective cohort study of adult patients with a histological confirmed glioblastoma (n=363), treated with standard treatment regimen at the Brain Tumor Center Amsterdam between 2000 and -2020. Severe haematological toxicity was defined as a CTCAE (version 5.0) grade ≥3. We used Pearson Chi-Square test to analyze differences in patient characteristics between the groups (no vs. severe toxicity) and paired samples T- Test to analyze fluctuations in cell counts. Univariate and multivariate logistic regression were used to identify patient- and treatment characteristics associated with severe hematological toxicity. Cox Proportional Hazards models were used to estimate Hazard Ratio’s for the association between survival and severe hematological toxicity. RESULTS Female gender (OR 8.05, 95%CI 2.96–21.89, p&lt;0.001) and older age (age &gt; 70 years; OR 2.44, 95%CI 1.12–5.31, p=0.025) were independent risk factors for severe toxicity. Concurrent and adjuvant temozolomide was discontinued in respectively 56% and 35% of the patients. In general, patients with severe hematological toxicity had a treatment delay of 22 ± 48 days. Of all patients with severe hematological toxicity during chemoradiation, 96% developed toxicity after ≥4 weeks of treatment (p&lt;0.001). Females who received highest temozolomide-doses (4th quartile) had a longer survival than females with low cumulative temozolomide doses (1st quartile). Patients, who developed severe toxicity had much more hospital visits (20; range 12–26), and were admitted more frequently to the hospital. Severe haematological toxicity was not related to survival (HR 1.04; 95%CI 0.74–1.45). CONCLUSION Female gender and age &gt;70 years are risk factors for severe hematological toxicity. Severe hematological toxicity relates to temozolomide exposure and results in a significant treatment burden for patients. Low temozolomide exposure results in decreased survival. Patient tailored therapy may result in better treatment outcomes.

Activity and safety of cabozantinib (cabo) in brain metastases (BM) from metastatic renal cell carcinoma (mRCC): An international multicenter study.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 310-310
Author(s):  
Laure Hirsch ◽  
Nieves Martinez Chanza ◽  
Subrina Farah ◽  
Ronan Flippot ◽  
Nityam Rathi ◽  
...  
Keyword(s):  
Response Rate ◽  
Local Therapy ◽  
Median Number ◽  
Clinical Activity ◽  
Recist 1.1 ◽  
Kaplan Meier ◽  
Best Response ◽  
Radiological Response ◽  
Modified Recist ◽  
International Multicenter Study

310 Background: Cabo shows robust clinical activity in mRCC. Patients (pts) with BM have been underrepresented in clinical trials and effective systemic therapy is lacking. We retrospectively characterized the clinical activity and toxicity of cabo in pts with BM from RCC. Methods: Consecutive medical records from mRCC pts with BM treated with cabo monotherapy across 15 institutions were reviewed. Pts were grouped by radiologic presence (cohort 1) or absence (cohort 2) of progressing intracranial metastases. Brain-directed local therapy was allowed but radiological confirmation of intracranial progression at cabo start was required in cohort 1. Radiological response rate was investigator-assessed by modified RECIST 1.1 for intracranial and RECIST 1.1 for extracranial responses. Time to treatment failure (TTF) and overall survival (OS) were estimated by Kaplan-Meier. Results: We identified 69 pts with BM from RCC, 25 (36%) in cohort 1 and 44 (64%) in cohort 2. Majority were IMDC intermediate/poor (87%) and received cabo as ≥2nd line (75%). Median time from mRCC diagnosis to BM was 19.1 months (mos) (IQR 4.4-39.5). Overall, median number of BM was 3 (range 1-27) and median size of largest lesion was 1.2 cm (range 0.2-6.6) with frontal (62%) and parietal (48%) as the most frequent localizations. Prior brain directed therapy was used in 65% and 93% of pts in cohort 1 and 2 respectively. Median follow-up after cabo initiation was 11 mos (range 4-72). Twenty three percent of pts remained on therapy while 52% discontinued for progression and 9% for toxicity. Intracranial response rate was 61% (95%CI 39%-80%), with 3 complete responses, for cohort 1 and 57% (95%CI 41%-72%) for cohort 2. Only 10% (n = 7) had intracranial progression as best response. For cohort 1, extracranial response was 52% (95%CI 31%-72%), median TTF was 9.9 mos (95%CI 5.9-14.0) and OS was 14.7 mos (95%CI 7.7-23.0). For cohort 2, extracranial response was 41% (95%CI 26%-57%), TTF was 9.0 mos (95%CI 4.6-11.4) and OS was 14.1 mos (95%CI 11.0-22.0). Most common adverse events were fatigue (77%) and diarrhea (46%). Eight pts received concomitant brain-directed treatment during cabo therapy without neurological toxicities. Conclusions: Cabo shows significant intracranial activity and acceptable safety profile in pts with BM from RCC. [Table: see text]

Clinical Experience of Decitabine in Elderly Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2792-2792 ◽  
Author(s):  
George F. Geils
Keyword(s):  
Elderly Patients ◽  
Subgroup Analysis ◽  
Response Rate ◽  
De Novo ◽  
Treatment Options ◽  
Group Versus ◽  
International Prognostic Scoring System ◽  
Hematological Toxicity ◽  
Age Group ◽  
Transfusion Independence

Abstract 2792 Poster Board II-768 Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients. The incidence of MDS increases with age, with limited treatment options for these patients. With advancing age, patients are generally less tolerant of treatment and suffer from more comorbidities. Important goals of therapy are to improve transfusion dependence and to delay progression of disease, with favorable toxicity. This subgroup analysis evaluated the effect of decitabine on overall response rate (ORR), duration of response, time to response, transfusion independence, and tolerability in subgroups of older patients (65-75 and >75 years of age). Methods: Data used in these analyses were from two previously published clinical trials (Steensma et al. J Clin Oncol, 2009 [DACO-020] and Kantarjian et al. Cancer 2006 [DACO-007]). In both trials, eligible patients were ≥18 years of age and had MDS (de novo or secondary) of any French-American-British subtype and an International Prognostic Scoring System score ≥0.5. In DACO-020, patients were treated with decitabine 20 mg/m2 IV daily for 5 consecutive days every 4 weeks. Response rate was assessed with the International Working Group (IWG 2006) criteria in DACO-020. In DACO-007, patients were treated with decitabine 15 mg/m2 IV over 3 hours every 8 hours for 3 consecutive days every 6 weeks. Response rate was assessed with the IWG 2000 criteria in DACO-007. Results: In DACO-020, baseline disease characteristics were generally similar between groups, except more patients in the 65-75 age group (n = 58) had RARS (19% vs. 4%) or RAEB (50% vs. 38%) and fewer had RA (12% vs. 38%) compared to patients in the >75 age group (n = 26). Further, more patients in the >75 group were transfusion dependent at baseline (77% vs. 57%). Grade 3-4 anemia, leukopenia, neutropenia, and thrombocytopenia were less frequent (22, 5, 35, and 22%, respectively) in patients in the 65-75 age group versus patients in the >75 age group (27, 8, 46, and 35%, respectively). Remarkably, however, there were no reports of febrile neutropenia in >75 age group (26% in the 65-75 age group). Conclusions: In this subgroup analysis, decitabine is an effective and generally well tolerated treatment strategy, even in elderly patients with MDS. Despite the advanced age, responses were more rapid and more durable in the mature elderly than younger patients. The slightly higher hematological toxicity did not translate into increased infectious risk, with no febrile neutropenic episodes in patients over age 75 in these studies. These data suggest that the goals of therapy do not need to be stratified by age, and support future trials of decitabine in elderly and other at-risk populations with MDS. Disclosures: Geils: Eisai Inc. : Speakers Bureau.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

Lenalidomide (LEN) Combined to Intensive Chemotherapy (IC) In AML and Higher Risk MDS with Del 5q. Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 508-508 ◽  
Author(s):  
Lionel Ades ◽  
Thomas Prebet ◽  
Aspasia Stamatoullas ◽  
Christian Recher ◽  
Romain Guieze ◽  
...  
Keyword(s):  
Phase I ◽  
Multiorgan Failure ◽  
Early Death ◽  
Cytogenetic Response ◽  
Median Number ◽  
Induction Treatment ◽  
Intensive Chemotherapy ◽  
Complex Karyotype ◽  
Recent Phase ◽  
Wbc Count

Abstract Abstract 508 Background: Contrary to the “5q syndrome”, prognosis of MDS with del 5q with increased BM blast % and/or additional cytogenetic abnormalities (abn) and of AML with del 5q (isolated or complex) is poor. Furthermore, del 5q is present in 40–50% of higher risk MDS and AML with complex karyotype. Those patients respond poorly to IC with 20–30% CR, of short duration (Estey, Hematologica 2000) and to azacytidine (AZA) (Mufti, ASH 2009, abstr n° 1755). Lenalidomide (LEN) yields hematological but also frequently cytogenetic CR in lower risk MDS with del 5q. In a recent phase II study of LEN in higher risk MDS or AML with del 5q, 28% responded, some with cytogenetic responses, but with significant myelosuppression (Ades, Blood 2008). This prompted us to combine IC and REV in this patient population. Methods: This still ongoing phase I/II study (Clinical trial.gov n° NCT00885508) combines induction DNR (45 mg/m2/d d1-3, escalated to 60 mg/m2/d d1-3) + AraC (200mg/m2/d d1-7) to LEN (10 mg/d d1-21)and G-CSF (from day 8 to end of aplasia) in IPSS int 2 or high MDS or AML with del 5q (isolated or not). Responders, ie CR, CRi or marrow CR according to AML criteria (Cheson JCO, 2003) receive 6 consolidation courses of DNR (45 mg/m2 d1), AraC (120 mg/m2/d×5) and LEN 10 mg/d d1-15, followed by maintenance LEN (14 days/month) until progression. After the first cohort at DNR 45 mg/m2/d d1-3 (n=31) proved safe, escalation to DNR 60 mg/m2/d during induction and consolidation courses was made (n=17). Results: Between Feb 2009 and April 2010, 48 pts from 11 centres were included: 22 Female, 26 Male, median age was 65 years (range 30–79), 36 (75%) AML and 12 (25%) RAEB-2 (WHO classification). 38/48 (79%) pts had complex Karyotype (median number of 6 abn (range 2–13) in addition to del 5q), 5 pts had isolated del 5q and 5 pts had del 5q+1 abn. 11 (23%) pts had therapy related disease. At inclusion, ECOG was 0 in 14 pts, 1 in 21 pts, 2 in 4 pts and 3 in 1 pt (8 missing data). Median baseline WBC, platelets and Hb level were 2.85 G/l (0.7-100), 45 G/l (11-213) and 8.7 g/dl (7.2-11.5) respectively (resp). 31 pts were included in the fist cohort (DNR 45 mg/m2) and 17 were included in the second cohort (DNR 60 mg). All but 7 pts received the planned schedule of LEN (21 days). Overall, 5 pts had early death related to severe sepsis in 3, multiorgan failure in 1 and myocardial infarction in 1 pt. Median duration of hospitalisation during induction treatment was 30.5 days (range 19–43). In responders, median ti me to ANC>1G/l and platelet >50G/l was 23 days (range 1–36) and 22 days (range 9–38), 19 d and 19 d, 24d and 24d in the whole cohort, in DNR45 cohort and in DNR60 cohort resp (p=0.1). Median number of RBC and platelet units transfused during induction treatment was 9 (4-16) and 7 (3-21), resp. 24 pts (50%) achieved CR, 1 achieved CRi (2%), 1 PR (2%) and 3 pts (6%) normalized PB count without marrow response, leading to an ORR of 29/48 (60%). Of the 17 pts with hematological CR/CRi evaluable for cytogenetic response, 8 (Including 4 complex karyotype, 3 isolated del 5q and 1 del5q+1 abn) achieved cytogenetic CR, 5 cytogenetic PR and 4 had no cytogenetic response. Eight of 12 (66%) MDS achieved CR/CRi compared to 17/36 (47%) AML (p=0.32). Four of 5 (80%), 4/5 (80%) and 17/38 (45%) pts with isolated del5q, del5q+1 abn and complex carytotype, resp, achieved CR/CRi (p=0.134). 17 of 31 (55%) pts in the DNR45 cohort achieved CR, vs 8/17 (47%) pts in the DNR60 cohort (p=0.76). Sex, ECOG status, Age, WBC count, Hb level, Platelet count had no effet on CR achievement. Among the 25 pts in CR, 14 relapsed and 2 died in CR (1 during consolidations and 1 after SCT). 1y DFS was 26.5% and significantly shorter in females (p=0.03) while other factors did not influence DFS. Estimated 2y OS was 30% and WHO diagnosis, Sex, Karyotype, and ECOG had no impact on OS. Conclusion: Intensive chemotherapy (IC) and LEN can be combined in higher risk MDS and AML with del 5q without unexpected additive myelosuppression or extra hematological DLT. In this cohort of elderly pts with very poor cytogenetics, The CR rate was 50%, higher than generally reported with CT alone in similar pts. DFS remained however short, suggesting that induction or consolidation therapy should be improved. Based on the better efficacy of DNR 90 mg/m2/d (Lowenberg et al, and Fernandez H et al, NEJM, 2009) in the chemotherapy of elderly AML, and the adequate tolerance in our DNR 60 cohort, we will increase the DNR dose to 90 mg/m2/d in a next patient cohort. Disclosures: Off Label Use: Lenalidomide in the treatment of AML and High risk MDS. Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Gemcitabine in Combination with Oxaliplatin (GEMOX) As a Salvage Regimen in Patients with Relapsed/Refractory Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1517-1517 ◽  
Author(s):  
Evren Ozdemir ◽  
Alma Aslan ◽  
Alev Turker ◽  
Ibrahim Barista ◽  
Ayse Kars
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Median Number ◽  
Hodgkin's Lymphoma ◽  
Hematological Toxicity ◽  
Hematologic Toxicity ◽  
Refractory Disease ◽  
Salvage Regimen ◽  
Overall Response

Abstract This study's objective was to evaluate the efficacy and safety of gemcitabine in combination with oxaliplatin (GEMOX) as a salvage regimen in patients with relapsed or refractory Hodgkin's lymphoma. Twenty-five patients were enrolled. All patients had received ≥ 2 prior chemotherapy regimens, had an ECOG performance status ≤ 2 and had adequate organ function. Patients received intravenous gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) on days 1 and 15, every 4 weeks. The median age was 29 years (range, 18-64) and 16 (68%) were male. Twenty-one (84%) had primary refractory disease (n=13) or relapsed within 12 months after initial therapy (n=8). All had previous platinum-based salvage chemotherapy (ICE, 23; DHAP, 2). Ten patients (40%) had relapsed/refractory disease following autologous stem cell transplantation (SCT). None had previous brentuximab vedotin treatment. Twenty-one (84%) patients were refractory or progressive on the last treatment. Median number of previous lines of chemotherapy was 2 (range, 2-4). Median number of GEMOX cycles administered to the patients was 3 (range, 2-6). Treatment response was evaluated with PET-CT before and 2-3 cycles after treatment, and those patients who demonstrated a response continued to receive a maximum of 6 courses of GEMOX or bridged to SCT. Of 25 patients, 2 (8%) had complete response, 9 (36%) had partial response and the remaining patients had refractory/progressive disease with an overall response rate of 44%. Seven of the 10 patients who had relapsed/refractory disease after autologous SCT achieved a response (CR, 2; PR, 5). The median time to progression for responding patients was 3 months (range, 1-40 months). One patient is disease free for 40 months. Three patients were successfully bridged to SCT (autologous, 2; allogeneic, 1). Main toxicity was hematological. Grade ≥ 3 hematologic toxicity occurred in 10 patients: thrombocytopenia (36%), neutropenia (16%) and anemia (8%). Among these, 7 had previous autologous SCT. One patient had grade 4 neutropenia and thrombocytopenia. Treatment cycle postponed in 6 patients without dose reduction because of hematological toxicity. Seven patients (28%) needed G-CSF support. One patient developed febrile neutropenia. No treatment-related deaths occurred. GEMOX was shown to be an effective salvage regimen in patients with relapsed/refractory Hodgkin's lymphoma, producing an overall response rate of 44%. It is an active regimen in patients who had relapsed/refractory disease after autologous SCT. Although, the median PFS time was short, some patients can be bridged to SCT and some can get long-term PFS. Hematological toxicity was common, especially in patients with previous autologous SCT. Disclosures Off Label Use: Gemcitabine in Hodgkin's Lymphoma Oxaliplatin in Hodgkin's Lymphoma.

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2518-2518
Author(s):  
Andrew Hantel ◽  
Niloufer Khan ◽  
Richard A. Larson ◽  
Lucy A. Godley ◽  
Michael J. Thirman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
De Novo ◽  
Median Number ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Induction Regimen ◽  
De Novo Aml ◽  
Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

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