scholarly journals Azacytidine Treatment in Patients with Acute Myeloid Leukemia/High-Risk Myelodysplastic Syndrome: Day-Hospital Management Compared to Home Care Setting

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4042-4042
Author(s):  
Giulio Trapè ◽  
Gioia De Angelis ◽  
Marco Morucci ◽  
Michela Tarnani ◽  
Cinzia De Gregoris ◽  
...  
Keyword(s):  
High Risk ◽  
Home Care ◽  
Care Setting ◽  
Hospital Admissions ◽  
Response Duration ◽  
Complete Response ◽  
Myelogenous Leukemia ◽  
Day Hospital ◽  
Median Response ◽  
Clinical Conditions

Abstract Introduction Treatment with Hypometilating Agents (HMA) of unfit patients (pts) with Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndromes (HR-MDS) is often difficult in the standard Day-Hospital (DH) setting, due to the number of hospital admissions required and the frail clinical conditions of pts. In the Viterbo province, accounting for 3612 Km 2 divided into 60 municipalities, is operative an Unit of Domiciliary Hematologic Care (UDHC) for clinical assistance to frail pts with hemopathies. Aims To evaluate the role of the UDHC compared to standard DH setting in the active frontline treatment with HMA +/- venetoclax (VTX) of pts with AML/HR-MDS. Methods All pts with newly diagnosed AML/HR-MDS unfit for intensive care and treated frontline with HMA from 1/2010 to 4/2021 were analysed. Results In this study period, 112 pts (62 AML/50 HR-MDS) received HMA (azacytidine in 105 cases and decitabine in 7 cases): six pts added VTX to HMA. As concern therapy management, 69 pts (61.6%) were treated in a standard DH setting and 43 (38.4%) were followed by UDHC: pts were allocated to DH or home care setting by responsible physician based on clinical conditions, comorbidities, caregiver availability and distance from hospital. The main features at baseline of HMA in the whole cohort and according to management are reported in the Table 1. Median interval from diagnosis to HMA initiation was 0.9 months (IQR 0.5 - 3.0). Median number of HMA cycles administered was 9 (IQR 4 - 16). The overall response rate (ORR), including complete response, partial response and hematologic improvement, was 43.7% (48/112 pts) in the whole cohort, without differences according to management [29/69 (42.0%) in DH vs 19/43 (44.1%) in home care, p=0.797]. Infections were also equally reported [46/69 pts (66.6%) in DH vs 31/43 (72.0%) in home care setting had at least 1 infection, p=0.362]. Median response duration of the whole cohort was 10.0 months (95%CI 5.7 - 14.2), without differences according to management [8.7 months (95%CI 7.0 - 10.3) in DH vs 13.0 months (95%CI 8.3 - 17.6) in home care, p=0.460]. Median Overall Survival (OS) of the whole cohort was 13.0 months (95%CI 9.7 - 16.2): median OS of pts treated in DH was 13.7 months (95%CI 9.9 - 17.4) compared to 13.0 months (95%CI 6.7 - 19.3) of pts managed by UDHC (p=0.753) (Figure 1). Conclusions Home care management of HMA for unfit AML/HR-MDS pts is feasible and effective, with results similar to those achievable in a standard DH setting: this approach is thus adequate to offer active therapies in a fraction of frail pts with AML/HR-MDS considered up to now ineligible. Figure 1 Figure 1. Disclosures Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

Outcomes of MDS Patients with Chromosome 7 Abnormalities Treated with 5-Azacytidine.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1449-1449 ◽  
Author(s):  
ZiYi Lim ◽  
Aloysius Y.L. Ho ◽  
Jonathon Samuel ◽  
Janet Hayden ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Median Survival ◽  
Who Classification ◽  
Response Duration ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Chromosome 7 ◽  
Response Criteria ◽  
Median Response

Abstract Chromosome 7 abnormalities occurring in isolation or as part of complex cytogenetics confer an adverse prognosis in patients with myelodysplastic syndromes (MDS). Preliminary clinical data from various groups has suggested that the use of 5-azacytidine, a DNA methyl transferase inhibitor, in this sub-group of poor risk patients may be associated with an improved clinical response. We report on a retrospective analysis on the outcomes of 31 MDS patients with chromosome 7 abnormalities treated with 5-azacytidine. 5-azacytidine was administered subcutaneously at 75mg/m2 daily for 7 days and each cycle was repeated every 28 days. The median age of the cohort was 61 years (range: 17–80). Based on the WHO classification, 4 patients (13%) were RCMD/RCMD-RS, 17 were RAEB I/II (55%), 8 patients had acute myeloid leukemia transformed from MDS (26%), an additional 2 patients had secondary MDS. The IPSS of the cohort was Int-1(n=1), Int-2(n=12), high-risk(n=18). 13(42%) patients had isolated chromosome 7 abnormalities, 8(58%) had chromosome 7 abnormalities as part of a more complex cytogenetic profile. 10 patients(33%) had previously been treated prior to therapy with 5 azacytidine. 5 patients were withdrawn from treatment after 1 cycle due to drug intolerance or disease progression and were excluded from further analysis. The remaining 26 patients received a median of 6 cycles of treatment (range: 2–28 cycles). Response criteria was based on the modified IWG response criteria for MDS (Cheson et al Blood 2007). 7 patients achieved a complete response (CR), 3 partial response (PR), with haematological improvement (HI) in a further patient. The median cycles of treatment before response was 2, with median response duration of 10.5 months (range: 4–20 months). Overall response rate (CR+PR+HI) was 6/12 (50%) for patients with isolated chromosome 7 abnormalities as compared with 5/14 (36%) for patients with complex cytogenetics (p=0.15). 7 patients had a complete cytogenetic response, with a further 2 patients achieving a partial cytogenetic response. These cytogenetic responses were observed in 4/12 patients with isolated chromosome 7, and 5/16 patients with complex cytogenetics. The median survival of the cohort was 19.8 months (95%CI: 16.3–23.3). Patients with isolated chromosome 7 abnormalities had median survival of 24.8 months (95%CI: 17.8–31.8) compared with those with complex cytogenetics (17.3 months, 95%CI: 8.3–26.3, p=0.10). In addition, patients achieving cytogenetic remission (complete or partial) had an improved overall survival when compared with non-responders (median OS: 24.8 vs 19.8 months, p=0.05). WHO classification, IPSS, patient age, and history of prior therapy were all not significant predictors of response or overall survival in this cohort. In summary, 5-azacytidine is able to induce high remission rates in a cohort of high risk MDS patients with chromosome 7 abnormalities.

Major activity of cladribine in patients with de novo B-cell prolymphocytic leukemia.

1997 ◽  
Vol 15 (1) ◽  
pp. 37-43 ◽  
Author(s):  
A Saven ◽  
T Lee ◽  
M Schlutz ◽  
A Jacobs ◽  
D Ellison ◽  
...  
Keyword(s):  
B Cell ◽  
Bacterial Infections ◽  
De Novo ◽  
Residual Disease ◽  
Active Agent ◽  
Response Duration ◽  
Complete Response ◽  
Median Response ◽  
Prolymphocytic Leukemia ◽  
Major Activity

PURPOSE De novo B-cell prolymphocytic leukemia (B-PLL) is a distinct clinicopathologic entity usually characterized by marked lymphocytosis, massive splenomegaly, an aggressive course, and refractoriness to therapy. Cladribine (2-chlorodeoxyadenosine [2-CdA]; Ortho Biotech, Raritan, NJ) is a newer purine analog with potent activity against indolent lymphoproliferative disorders. PATIENTS AND METHODS We treated eight patients with cladribine 0.1 mg/kg/d for 7 days by continuous infusion or 0.14 mg/kg/d over 2 hours for 5 days, every 28 to 35 days, for a median of three courses (range, two to five). There were five men and three women, with a median age of 62 years and a median pretreatment duration of 6 months; four patients were previously untreated. RESULTS All eight patients were assessable: five achieved a complete response with a median response duration of 14 months (range, 1+ to 55+), and three achieved a partial response with a median duration of 3 months (range, 1 to 3). Of four patients who achieved a complete response and in whom a peripheral-blood immunophenotypic analysis was performed, two had no circulating B-PLL cells and one had no residual disease on Southern blot analysis. Myelosuppression and infection were the major toxicities: three patients developed grade 3 or 4 myelosuppression, four had bacterial infections, and two had herpes zoster infections. CONCLUSION In this small study of patients with de novo B-PLL, cladribine was an active agent that induced a high overall and complete response rate. These results require confirmation in larger numbers of B-PLL patients.

Long-Term Disease Control in Patients with Primary Central Nervous System Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3600-3600
Author(s):  
Ingo Schmidt-Wolf ◽  
Hendrik Pels ◽  
Annika Jürgens ◽  
Sabine Rogowski ◽  
Axel Glasmacher ◽  
...  
Keyword(s):  
Overall Survival ◽  
Central Nervous System Lymphoma ◽  
Response Duration ◽  
Complete Response ◽  
High Dose ◽  
Survival Fraction ◽  
Median Response ◽  
Kaplan Meier ◽  
Time To Treatment Failure

Abstract Objectives: A pilot phase II trial was performed to evaluate response rate, response duration, overall survival, and toxicity in primary central nervous system lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From 09/1995 to 12/2002, 65 patients with PCNSL (median age 62 years) were enrolled into a pilot/phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX) (cycles 1,2,4,5) and cytarabine (ara-C) (cycles 3,6) based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide) was combined with intraventricular MTX, prednisolone and ara-C. Primary endpoint was time to treatment failure (TTF), secondary endpoints were response, overall survival, response duration, 5-year-survival fraction and (neuro)toxicity. Results: 34 patients were male, 31 female. Sixty-one of 65 patients were evaluable for response. Of these, 37 (61%) achieved a complete response (CR), 6 (10%) complete response/unconfirmed, and 12 (20%) progressed under therapy. Overall response rate was 71% for all patients and 86% for patients younger than 61 years. Six (9%) out of 65 patients died due to treatment-related complications. Follow-up time is 78 to 151 months in surviving patients (median 100 months). Kaplan Meier estimates for median time to treatment failure (TTF), median overall survival and median response duration are 22 months, 54 months and 37 months, respectively. For patients aged 60 years or older, the respective numbers were 7 months, 34 months and 30 months; in patients younger than 60 years, the Kaplan Meier estimate for TTF is 49 months, median overall survival and median response duration have not yet been reached. The 5-year survival fraction is 72% in patients < 60 years and 24% in older patients. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 19% of the patients. At present, 17/30 (57%) of younger and 4/35 (9%) elderly patients are still alive. Only 5/30 (17%) of younger, but 19/35 (54%) of elderly patients received radiation salvage therapy at relapse. In 2/65 (3%), secondary cancers developed. In the subgroup of patients with long-term survival (n=17/30 under 61 years), 12 had an ongoing response, 1 an isolated CNS relapse (resolved by radiation), 1 an isolated ocular relapse (resolved by ocular radiation) and 3 a pure systemic relapse without CNS involvement (all resolved by systemic chemotherapy). Eleven of these 17 patients could be investigated by comprehensive neuropsychological testing, which revealed normal cognitive function in all of them. Conclusions: Primary chemotherapy based on high-dose MTX and ara-C is highly efficient in PCNSL. A substantial fraction of patients < 60 years can obviously be cured with this regimen.

Combination chemotherapy with temsirolimus and trabectedin in patients with heavily pretreated clear cell carcinoma of the ovary.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16519-e16519
Author(s):  
Masashi Takano ◽  
Hiroko Kouta ◽  
Naoki Sasaki ◽  
Kazuya Kudoh ◽  
Tsunekazu Kita ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Mammalian Target Of Rapamycin ◽  
Response Duration ◽  
Complete Response ◽  
Marine Natural Product ◽  
Median Response

e16519 Background: Clear cell carcinoma (CCC) of the ovary showed exceedingly chemo-resistant phenotype, especially in the case with recurrent or refractory to previous therapy. An inhibitor against the mammalian target of rapamycin (mTOR), temsirolimus, has been reported to be effective in renal CCC. Additionally, a marine natural product, trabectedin, had activity against recurrent ovarian cancers. We evaluated the effect of combination therapy with temsirolimus and trabectedin for patients with recurrent/refractory CCC of the ovary. Methods: Patients with recurrent/refractory CCC of the ovary were treated with weekly regimen using two drugs: 10mg/m2 of temsirolimus and 0.15mg/m2 of trabectedin (3 weeks, one week rest) with written informed consents. Treatment was continued until development of progressive disease (PD) or unmanageable adverse effects. Responses were evaluated by RECIST criteria, and adverse effects were analyzed by NCI-CTCAE v4.0. Results: A total of 12 patients treated with the regimen, and there were no cases that discontinued the therapy due to toxicities. Median age was 60 years (range: 42-69), and median number of previous chemotherapy was 3 (range: 1-5). All cases were assessable by RECIST and CTCAE. One patient (8%) had a complete response (CR), and another (8%) achieved a partial response (PR), and 4 patients (33%) had stable disease (SD) beyond three months, resulting in clinical benefit rate (CBR; CR+PR+SD>3month) of 50%. Median response duration in CBR case was 3.5 months (range: 3-12+). There were no cases that developed toxicities more than grade2. Conclusions: The present preliminary study demonstrated combination therapy with temsirolimus and trabectedin was effective in patients with recurrent/refractory CCC of the ovary. These results warrant further study in such clinical settings.

A pilot study of supraphysiologic testosterone (T) and oral etoposide (E) in men with castrate-resistant prostate cancer (CRPC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 45-45
Author(s):  
Michael Thomas Schweizer ◽  
Emmanuel S. Antonarakis ◽  
Hao Wang ◽  
Avery N. Spitz ◽  
Haiyi Cao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Objective Response ◽  
Response Duration ◽  
Complete Response ◽  
Dna Breaks ◽  
Median Response ◽  
Ablative Therapies ◽  
Neutropenic Sepsis ◽  
Topoisomerase 2 ◽  
Psa Response

45 Background: Prostate cancer (PC) cells become resistant to chronic castration via an adaptive increase in androgen receptor (AR) expression, a liability that can be exploited therapeutically. Mechanistically, supraphysiologic androgens can induce PC cell death through topoisomerase 2 (topo2) mediated double-strand DNA breaks and disruption of DNA relicensing due to persistence of AR at origins of replication during the cell cycle. Methods: We evaluated parenteral T in combination with the topo2 inhibitor E in men with CRPC and low metastatic burden (≤5 bone and <10 soft tissue metastases). To rapidly cycle from supraphysiologic (>1500 ng/dL) to near castrate T levels, men received intramuscular T cypionate 400 mg on day (D) 1 and oral E 100 mg D 1-14 of a 28 D cycle. After 3 cycles, men with declining PSA could continue T alone every 28 D. The primary endpoint was PSA response, defined as a PSA below baseline, after cycle 3. Secondary endpoints included objective response rates and safety. Results: Sixteen men enrolled of which 14 completed 3 cycles of T+E and were evaluable for response. 7/14 went on the T-only expansion stage. After 3 cycles, 6/14 men had a PSA response. 7 (50%) had a PSA response at any timepoint [4 (29%) had PSA declines ≥50%] (table). In men with RECIST-evaluable disease, 2 had progressive and 3 had stable disease (SD), 4 had partial (PR) and 1 had a complete response (CR). Median response duration was 248 D (range, 80 to 359 D). Post T, 10/12 men had a PSA decline to subsequent androgen ablative therapies. Most adverse events (AEs) were ≤grade 2 and considered effects of E. One man died from neutropenic sepsis before completing the 1st cycle. AEs possibly related to T included lower extremity edema (n=1), priapism (n=1) and asymptomatic pulmonary embolism (n=2). No one developed new pain on T. Conclusions: T with or without E demonstrated preliminary efficacy in patients with CRPC as manifested by PSA and objective responses. This regimen is generally safe. Cyclic T-based therapies warrant further study. Clinical trial information: NCT01084759. [Table: see text]

Phase II Trial of the Bonn Polychemotherapy Protocol with Deferred Radiotherapy in Patients with Primary Central Nervous System Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2453-2453
Author(s):  
Ingo G.H. Schmidt-Wolf ◽  
Annika Juergens ◽  
Hendrik Pels ◽  
Axel Glasmacher ◽  
Holger Schulz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Central Nervous System Lymphoma ◽  
Response Duration ◽  
Complete Response ◽  
High Dose ◽  
Survival Fraction ◽  
Median Response ◽  
Kaplan Meier ◽  
Time To Treatment Failure

Abstract Objectives: The trial was performed to evaluate response rate, response duration, overall survival, and toxicity in primary central nervous system lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From 09/1995 to 12/2002, 88 patients with PCNSL (median age 62 years) were enrolled onto a pilot/phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX) (cycles 1,2,4,5) and cytarabine (ara-C) (cycles 3,6) based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide) was combined with intraventricular MTX, prednisolone and ara-C. Primary endpoint was time to treatment failure (TTF), secondary endpoints were response, overall survival, response duration, 5-year-survival fraction and (neuro)toxicity. Results: Eighty-four of 88 patients were evaluable for response. Of these, 46 (54%) achieved complete response (CR), 4 (5%) complete response/unconfirmed, 8 (10%) partial response (PR), and 14 (17%) progressed under therapy. Seven (8%) out of 84 patients died due to treatment-related complications. In five (6%) of 84 patients therapy had do be discontinued due to severe treatment related complications. Follow-up is one to 124 months (median 42 months). Kaplan Meier estimates for median time to treatment failure (TTF), median overall survival and median response duration are 19 months, 55 months and 37 months respectively. For patients aged 60 years or older, the respective numbers were 9 months, 34 months and 24 months; in patients younger than 60 years Kaplan Meier estimate for TTF is 49 months, median overall survival and median response duration have not been reached yet. The 5-year survival fraction is 72% in patients < 60 years and 24% in older patients. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 20 (23%) patients. In a subgroup of patients (n=23) treated with chemotherapy alone serial neuropsychological testing showed no chemotherapy related cognitive decline in any patient. However, 8 out of 13 documented elderly patients treated with cranial irradiation as salvage therapy developed severe cognitive deficits. Conclusions: Primary chemotherapy based on high-dose MTX and ara-C is highly efficient in PCNSL. A substantial fraction of patients < 60 years can obviously be cured with this regimen.

Early Relapses in Primary CNS Lymphoma (PCNSL) without Intraventricular Treatment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4440-4440
Author(s):  
Ingo G.H. Schmidt-Wolf ◽  
Hendrick Pels ◽  
Annika Jurgens ◽  
Axel Glasmacher ◽  
Holger Schulz ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Response Duration ◽  
Complete Response ◽  
High Response Rate ◽  
High Rate ◽  
Cns Lymphoma ◽  
High Dose ◽  
Median Response ◽  
Kaplan Meier ◽  
Intraventricular Treatment

Abstract Background: A systemic and intraventricular polychemotherapy regimen (“Bonn protocol”) with deferred radiotherapy had resulted in durable responses in 75% of patients < 60 years with primary CNS lymphoma (PCNSL), but had been complicated by a high rate of Ommaya reservoir infections. Purpose: Here, efficacy and toxicity of this regimen but without intraventricular treatment was evaluated in PCNSL. Patients and Methods : From 08/03 to 11/05, 18 patients with PCNSL < 60 years (median age 53 years) were treated within a phase II trial with a high-dose methotrexate (MTX; cycles 1,2,4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Results: Study accrual was prematurely stopped in 11/05 due to a high rate of early relapses. Seventeen/18 patients were assessable for response: Nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu), two (12%) partial response (PR), four (24%) showed progressive disease (PD); in one treatment was stopped due to toxicity. Median follow-up is 23 months; Kaplan-Meier estimates for median response duration were ten months only in responding patients and for median time to treatment failure (TTF) eight months in the whole group; median overall survival (OS) has not yet been reached. Systemic toxicity was mainly hematologic. Conclusions: In patients < 60 years with PCNSL polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with inclusion of intraventricular treatment.

Therapeutic Benefit of Decitabine, a Hypomethylating Agent, in Patients with Myeloproliferative Neoplasm in Blastic Phase/Acute Myeloid Leukemia (MPN-AML), Accelerated Phase (MPN-AP), and DIPSS-Plus High Risk Primary Myelofibrosis (PMF)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3186-3186
Author(s):  
Talha Badar ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Median Time ◽  
Blood Count ◽  
Response Duration ◽  
Median Number ◽  
Second Line ◽  
Median Response ◽  
Line Therapy

Abstract Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of hypomethylating agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a hypomethylating agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active agents are needed to improve overall outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4158-4163 ◽  
Author(s):  
Pierre Fenaux ◽  
Azra Raza ◽  
Ghulam J. Mufti ◽  
Carlo Aul ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Myelodysplastic Syndrome ◽  
Active Agent ◽  
Response Duration ◽  
Phase 2 ◽  
Median Response ◽  
Multicenter Phase ◽  
Phase 2 Study ◽  
Grade 3

Abstract This multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.

Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid

Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1266-1269 ◽  
Author(s):  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
Manuel Aivado ◽  
Alf Bernhardt ◽  
Barbara Hildebrandt ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Retinoic Acid ◽  
Myelodysplastic Syndromes ◽  
Response Duration ◽  
Therapeutic Benefit ◽  
Myelogenous Leukemia ◽  
Median Response ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro. We treated 18 patients with myelodysplastic syndromes (MDS) and AML secondary to MDS (sAML/MDS) with VPA monotherapy (serum concentrations 346-693 μM [50-100 μg/mL]). Five patients received VPA and ATRA (80 mg/m2/d, days 1-7, every other week). Response according to international working group (IWG) criteria was observed in 8 patients (44%) on VPA monotherapy, including 1 partial remission. Median response duration was 4 months (range, 3-9 months). Four of 5 patients relapsing were treated with VPA + ATRA, 2 of them responding again. Among 5 patients receiving VPA + ATRA from the start, none responded according to IWG criteria, but 1 patient with sAML/MDS achieved a marked reduction in peripheral and marrow blasts. Thus, VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.

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