Thrombopoietin Analogs In ITP Patients Daily Practice: Treatment Profile, Efficacy and Safety

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4749-4749
Author(s):  
Maria Eva Mingot-Castellano ◽  
Dana Diaz-Canales ◽  
Fernando Fernandez-Fuertes ◽  
Maria Perera-Alvarez ◽  
Isabel Caparros-Miranda ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Response Rate ◽  
The Other ◽  
Lower Limbs ◽  
Efficacy And Safety ◽  
Off Label ◽  
Chronic Itp ◽  
Treatment Profile

Rationale and Objectives Thrombopoietin analogues (TPOa) are an effective alternative of treatment in patients with refractary primary immune thrombocytopenia (ITP) or chronic ITP patients with esplenectomy contraindication. Although this is their ITP indication, there are other clinical situations in day by day ITP patients clinical management in where these drugs are being used off label. We describe the treatment profile, efficacy and safety of TPOa in ITP patients in ours centers. Material and Methods ITP patients diagnosed and treated with TPOa between March 2009 and May 2013 in five centers. The study variables were: age, sex, ITP status and bleeding profile, treatment lines before TPOa, reason to use them, baseline platelet and hemoglobin, response rate, time to response, treatment duration, bleeding and adverse events. Results We analyze 62 patients (35 women), median age 51.5 years-old (10-88 years old). 32.5% of patients present refractory chronic ITP, 51% non splenectomized chronic ITP, 10% persistent and 7.5% recently diagnosed ITP. 50% receive 3 or more treatment lines before TPOa. 8 patients receive treatment because of surgery, chemotherapy or radiotherapy (1 newly diagnosed, 1 persistent and 6 chronic non splenectomized ITP). The rest are treated because of bleeding and/or thrombocytopenia severity. Reasons to non splenectomize patients are comorbidities (52.8%), patient refusal (24.5%) or non chronic ITP criteria. Median follow-up of TPOa treatment is 75 weeks (range 3-215 weeks), 91%. response rate. Median time to reach platelet count higher than 30x10e9/L is 2 weeks (1-22 weeks). Mean stable dose: eltrombopag 48.5+/-17mg/day and Romiplostin 3.4 +/-2.64mcg/kg/week with no difference between splenectomized and non splenectomized patients. 67% of chronic ITP patients present an stable response. 37% of patients require resque treatment during the follow-up. 6 (12%) patients with chronic ITP have discontinued TPOa after 6 to 24 months and they stay in response. 24 patients received only romiplostin, 22 only eltrombopag and 16 patients have been treated with the two available TPOa. One patient did not respond to any of them, another responded to romiplostin and not to eltrombopag, two to eltrombopag and not to romiplostin and the remaining 12 respond to both. 82% of patients present no bleeding event during TPOa treatment. 6 patients receive secondary prophylaxis with anticoagulants drugs and other 6 ones with antiplatelet during TPOa treatment with no haemorragic problems. In the 40 romiplostin treatments, the most common side effect was headache. We find only one case of transient elevation of transaminases among the 38 eltrombopag treatments. In 57 patients bone marrow aspirate was performed before TPOa indication, only 26 bone marrow biopsy were done. In two of these patients are described reticulin fibrosis grade 1 before treatment. No information on subsequent tests. We describe three thromboembolic events. One pulmonary embolism (PE) in a woman with vascular risk factors and history of lung cancer. The other two events were lower limbs venous thrombosis in young subjects with no risk factors or abnormally high platelet counts. Diagnosis of 1 aplastic anemia and 1 myeloma during treatment with TPOa. Four exitus, 2 intracranial bleedings, 1 PE and 1 of unknown cause. 24% of patients treated with romiplostin are on out-hospital treatmen, in most cases for reasons not related to patient autoself-treatment capacity. Conclusions New thrombopoietic agents are indicated in refractory chronic ITP or chronic ITP patients with splenectomy contraindications. There are other situations in ITP evolution where they could be useful. These off label situations can become even more prevalent than so far established indication. In our experience, these drugs are effective and safe in these others conditions but treatment should be individualized based on patient needs and comorbidities. Lack of response to one TPOa agent does not mean the other one inefficiency. Disclosures: No relevant conflicts of interest to declare.

Azacitidine As Front-Line Therapy in AML: Results From Spanish National Registry. Alma Study Investigators

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3593-3593 ◽  
Author(s):  
Fernando Ramos ◽  
Violeta Martinez-Robles ◽  
Joan Bargay ◽  
Guillermo Deben ◽  
Ana Garrido ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Response Rate ◽  
Daily Practice ◽  
Front Line ◽  
Bone Marrow Blast ◽  
Off Label ◽  
Multilineage Dysplasia ◽  
Line Therapy

Abstract Abstract 3593 Azacitidine (AZA) is currently being used in AML patients (Pts) not deemed candidates for intensive chemotherapy. Most of this usage follows approved drug label by EMA, but off-label usage is not uncommon in Pts with >30% bone marrow blast (BMB) cells. Clinical trials are now comparing AZA vs. conventional care in selected populations, and data from daily practice may shed light on the generalizability of their results. A retrospective nationwide study was set up in Spain in order to evaluate the population of AML Pts that is receiving AZA as front-line therapy (Rx) in Spain, its patterns of usage, effectiveness and safety in daily practice conditions, as well as the factors linked to overall response rate (ORR) and overall survival (OS). Only Pts treated before Dec/2010 could be included in this study, that was approved by the Spanish Medicines Agency (AEMPS, code ACL-AZA-2011–01). Data were collected from Oct/2011 to Jan/2012 and analyzed as of Jun/2012. ORR was evaluated according to both ELN-2010 criteria for AML as well as IWG-2006 criteria for MDS (in order to assess the impact of PB changes), OS measured from 1st cycle of AZA to death or last follow-up, and toxicity coded according to NCI CTCAEv3.0. One-hundred and ten untreated Pts (79 M/31 F, median age 75, range 56–89) were recruited from 22 academic and community sites. Comorbidity was present in 96 Pts (cardiac 43, hepatic 10, renal 3, diabetes 26, other neoplasms 18, etc.), ECOG being ≥2 in 33. Thirty Pts had an antecedent hematological disorder. Five cases had recurrent genetic abnormalities (NPM1-mutated AML in 4), 61 had MDS-related AML, 16 therapy-related AML and 28 AML not otherwise specified. Cytogenetics (Cyto) was available in 95 (86.4%): 48 diploid and 47 abnormal. MRC-2010 cyto category was favourable in 1, intermediate in 64 and adverse in 30. Median WBC at Dx was 3.3 x10E9/L (0.8–172.4), WBC before 1st AZA cycle 2.8 (1.0–175.0), platelet count 56 (7–467), PB blast 4.0% (0–100) and hemoglobin 91 g/L (48–142). Sixty-four Pts (58.2%) had BMB>30% (median 35.0%, range 15.0–98.0%). Median time from Dx to Rx was 19.5 days (0–411). Pts received 745 AZA cycles (median 4, range 1–29; ≥6 cycles 45.4%, ≥12 cycles 18.8%), but 30.9% received ≤2 because of disease progression or toxicity. 7.2% received concomitantly hydroxiurea for WBC control. Route of administration was EV in 5.8%, home administration took place in only 1.5%, and AZA was given as inpatients in 27.3% of the cycles. The no. of days of AZA Rx was 7 in 63.6% of the cycles, week-end off Rx being common place (5–2–2 schedule in 71.9%). Median AZA daily dose was 73.6 mg/sqm (<50 in 2.7%). During follow-up (median 8.6 months, 0.1–48.7), 56 Pts progressed (39 on and 17 off-Rx). In 18, response was not evaluable (lack of BM assessment or death before 8 weeks). Best ORR according to IWG-2006 was 44.5% and 53.3% in the ITT and evaluable populations, respectively, while ORR according to ELN-2010 was 17.3% and 20.7%, respectively. Complete response rate (including CRm/CRi) was 15.5% and 18.5%, respectively, with both criteria. Platelet count duplication after 1st cycle predicted ORR with IWG-2006 (82.4% vs. 33.8%, p=0.001, Fisher) but this was less evident with ELN-2010 (41.2% vs., 18.3%, p=0.057, Fisher). Median OS from 1st AZA cycle was 8.1 months (CI95% 5.3–10.9, range 0.1–47.9; OS at 12 months 36.7%, OS at 24 months 7%), OS from Dx 9.5 (CI 6.0–10.0, 0.1–48.7) and PFS 7.2 (CI 4.7–9.8; 0.1–29.5). Multivariate analysis showed that the best predictors of OS in our series were: ECOG ≤1, BMB ≤30%, a diploid cyto and WBC before 1st AZA cycle <10.0xE9/L. GFM score (Park et al, 2008), but not MLD, MDS-related AML or AZA dose, also predicted OS (p<0.001, Logrank). As expected, responders lived longer than non-responders, but discrimination was better for IWG-2006 (HR=2.84) than ELN-2010 (HR=2.32), suggesting that a PB response may also impact survival in AML. Six-hundred thirty-eight AEs were reported (25.9% SAEs and 36.7% grade III-IV), most commonly infectious (25.5%), hematological (19.3%), gastrointestinal (18.3%) and cutaneous (11.8%). CONCLUSION: OS of AML Pts treated with AZA seems promising, although it depends on ECOG, BM blast proportion, cytogenetics and WBC before 1st AZA cycle. After adjusting for cytogenetics, multilineage dysplasia does not result informative for OS in this population. Disclosures: Ramos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Azacitidine in AML (even without multilineage dysplasia or with more than 30% bone marrow blast cells). Deben:Celgene: Honoraria. Colado:Celgene: Honoraria.

scholarly journals Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Waldenstrom's Macroglobulinemia Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 46-46
Author(s):  
Daobin Zhou ◽  
Jie Jin ◽  
Zheng-zheng Fu ◽  
Shuhua Yi ◽  
Wei Li Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
B Cell ◽  
Response Rate ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Major Response ◽  
Grade 3 ◽  
Waldenström's Macroglobulinemia

Abstract Background Waldenstrom's Macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with immunoglobulin M (IgM) monoclonal gammopathy. Bruton's tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone, particular in patients harboring MYD88 L265P mutations. However, due to target selectivity issue, Clinical uses of early BTK inhibitors are still compromised with off-target activities to many other kinases besides BTK. Orelabrutinib is a novel, highly potent small molecule inhibitor of BTK with superior selectivity for B-cell malignancies and autoimmune diseases. Preliminary efficacy and safety data of ICP-CL-00105 in relapsed/refractory WM patients are presented here. Methods ICP-CL-00105 is a single arm, multiple centers, open label, phase 2 study in clinical and histopathological confirmed patients with R/R WM requiring treatment per IWWM-7. MYD88 and CXCR4 mutations were assessed in bone marrow samples at baseline. Orelabrutinib at a daily dose of 150mg was administered orally until disease progression or unacceptable toxicity. Blood samples for IgM were assessed at baseline and every cycle for 6 cycles and every 3 cycles thereafter by central lab. Responses were assessed in accordance with IWWM-6 and NCCN guidelines. The primary endpoint was major response rate (MRR) as assessed by IRC. Key secondary endpoints were MRR as assessed by investigator, overall response rate (ORR), duration of major response (DOMR), progression-free survival (PFS), OS, changes in IgM levels from baseline, improvement on hemoglobin levels and safety. Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) were assessed according to NCI CTCAE v4.03. Results As of June 1, 2021, for the 47 patients the median follow-up duration was 10.5 months. The median age was 63 years (range, 56-68 years), 40 patients (85.1%) were male. 87.2% of patients were at intermediate or high risk according to the Prognostic Scores (IPSS). The proportion of patients with MYD88 L265PCXCR4 wildtype was 83% at baseline. With a median duration of treatment of 9.2 months, MRR was 74.5% as assessed by investigator. ORR was 87.2% with 97.9% patients achieved disease control. The estimated 12-month DOMR were 89.5%. The estimated 12-month PFS and OS were 88.0% and 92.3%, respectively. The median PFS and median OS have not been reached. The MRR was higher in patients with MYD88 L265PCXCR4 wildtype (79.5%). The median IgM level was 30.3g/L at baseline. The decline in the serum IgM levels from baseline were observed with a median reduction by 79.0% (IQR: -89.4, -57.2). The median hemoglobin level at baseline was 102g/L. Durable improvement in hemoglobin levels was found in 83% of patients with a median maximal improvement of 40g/L (IQR: 24.0, 62.0). Safety data were summarized by the cutoff date of June 1, 2021. The most commonly reported AEs were thrombocytopenia (27.7%)，neutropenia (14.9%), leukopenia (10.6%), upper respiratory infection (14.9%)，weight increased (14.9%), influenza-like disease (12.8%) and rash (10.6%). Most reported AEs (89.5%) were grade 1-2. 16 patients (34.0%) reported grade ≥ 3 TEAE while 9 patients (19.1%) reported grade ≥ 3 TRAE. There was no reported grade ≥3 atrial fibrillation and/or atrial flutter, or grade ≥3 diarrhea. Only One TRAE (2.1%) resulted in drug discontinuation. Conclusion Orelabrutinib has demonstrated substantial efficacy in treating r/r WM patients under short-term follow-up. It has shown favorable safety and tolerability profile with limited off-target adverse effects. It has the potential to be a promising treatment option for r/r WM patients. Disclosures Hu: Astellas Pharma, Inc.: Research Funding. Tian: Innocare pharma: Current Employment. Zhu: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment. Zhao: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment.

scholarly journals Circulating Proangiogenic Cell Activity Is Associated with Cardiovascular Disease Risk

2012 ◽  
Vol 17 (9) ◽  
pp. 1163-1170 ◽  
Author(s):  
Kreton Mavromatis ◽  
Konstantinos Aznaouridis ◽  
Ibhar Al Mheid ◽  
Emir Veledar ◽  
Saurabh Dhawan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Bone Marrow ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cell Activity ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cvd Risk ◽  
The Relationship

Vascular injury mobilizes bone marrow–derived proangiogenic cells into the circulation, where these cells can facilitate vascular repair and new vessel formation. We sought to determine the relationship between a new biomarker of circulating bone marrow–derived proangiogenic cell activity, the presence of atherosclerotic cardiovascular disease (CVD) and its risk factors, and clinical outcomes. Circulating proangiogenic cell activity was estimated using a reproducible angiogenic colony-forming unit (CFU-A) assay in 532 clinically stable subjects aged 20 to 90 years and ranging in the CVD risk spectrum from those who are healthy without risk factors to those with active CVD. CFU-A counts increased with the burden of CVD risk factors ( p < 0.001). CFU-A counts were higher in subjects with symptomatic CVD than in those without ( p < 0.001). During follow-up of 232 subjects with CVD, CFU-A counts were higher in those with death, myocardial infarction, or stroke than in those without (110 [70–173] vs 84 [51–136], p = 0.01). Therefore, we conclude that circulating proangiogenic cell activity, as estimated by CFU-A counts, increases with CVD risk factor burden and in the presence of established CVD. Furthermore, higher circulating proangiogenic cell activity is associated with worse clinical outcome in those with CVD.

Retrospective Analysis of 1230 Patients of Immune Thrombocytopenic Purpura Reporting to a Tertiary Care Hospital in India from 1992–2004.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5294-5294
Author(s):  
Dharma R. Choudhary ◽  
Rajat Kumar ◽  
R. Saxena ◽  
Manoranjan Mahapatra ◽  
Atul Kotwal ◽  
...  
Keyword(s):  
Developing Countries ◽  
Response Rate ◽  
Tertiary Care Hospital ◽  
Tertiary Care ◽  
Cost Effective ◽  
Repeated Measure ◽  
Care Hospital ◽  
Chronic Itp ◽  
Acute Itp

Abstract Background: There is very little published epidemiological data from developing countries regarding ITP and no large series from India. The aim of the study was to analyze the presenting features, response to different therapeutic options and suggest cost effective therapy. Method: The records of hematology department of All India Institute Of Medical Science were analyzed from January 1992 to June 2004. This is a premium tertiary care hospital in India. Diagnosis of ITP was made according to the standard criteria. Response criteria: complete response was defined as a platelet count increase to 100x109 /l or more, for at least 2 months: partial response was defined as doubling of platelet counts from initial levels and &gt; 50x 109/l for at least 2 months; no response included none of the above. Statistical methods: Database was created in MS Access and SPSS ver 11 was used for statistical analysis. Descriptive statistics were calculated and appropriate tests of significance like Chi Square, repeated measure linear model were carried out. Results: During the study period, 1230 patients of ITP were seen in hematology department, with a median age of 19.6 years (range 0.9–80). Females were 51.1% and males 48.9%. Median follow-up was of 9 months (range 0–178). Presenting features were: skin bleed − 91.1%; mucosal bleed − 57.5%; hematuria − 7.2%; gastrointestinal bleed − 12.5% and intracraniall bleed − 2.8%. Per-vaginal bleeding − 31.2 % of females. History of preceding viral fever was seen in 13.1% and palpable spleen in 2.5%. The mean platelet counts at presentation were 34+ 18.3x109/l. There were 595 (48.4%) patients of acute ITP and 635 (51.6%) patients of chronic ITP. Childhood ITP (age ≤ 12 yr) was seen in 46.5% and adult ITP in 53.5%. Response to therapy: Prednisolone was given to 99.6% patients with response of 57.3 %; Intravenous gamma globulin was given to 8.9% with response in 63.6%. Splenectomy was performed in 5% of acute ITP and 15.1% of chronic ITP (p = 0.00). The overall number of splenectomies was 126, with a response rate of 83.3%. Of these 126, acute ITP constituted 23.8% while chronic ITP formed 76.2% of cases. There was no statistically significant difference in response rate in these two groups (p =0.575). Danazole was given to 66 patients with response in 44%. Various other modalities of treatment were given to 24 patients (Anti D-14; Dapsone-2; Cyclosporin-2; Azathioprine-5; and Vincristine with Cyclophosphamide -1 patient), with a response in 25% of patients. The overall response rate with all treatment modalities was 68%: in childhood ITP − 65% and in adult ITP − 70.5%. Childhood ITP did not respond as expected, possibly due to referral bias of more refractory cases being referred to the center. The values of platelets showed a continuous increase during follow up and this increase was statistically significant (P=0.000 for all, Repeated measure model). Conclusion: Pattern of ITP in India is similar to that seen in other centers. In this study Prednisolone was given as first line agent to almost all patients with response in 57.3%; Splenectomy were done in 10.2% of prednisolone refractory or dependent patients with a response in 83.3%. These should form the primary modalities of therapy in developing countries. Significant numbers of patients were refractory to above-mentioned modalities and thus there is a requirement for other cost-effective therapies.

Efficacy of Cyclosporine Treatment in Patients with MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4608-4608
Author(s):  
Alina Kokhno ◽  
Elena Parovitchnikova ◽  
Elena Mikhailova ◽  
Yulia Olshanskaya ◽  
Irina Kaplanskaya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stable Disease ◽  
Response Rate ◽  
Bone Marrow Failure ◽  
Normal Karyotype ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy

Abstract Myelodysplastic syndrome (MDS) represents a heterogenous group of myeloid neoplasms characterized by abnormal differentiation and maturation of myeloid cells, bone marrow failure and genetic instability. The recent clinical and laboratory investigations suggest that MDS is closely related to diseases in which the bone marrow failure is mediated at least in part by the immune system. The are few studies concerning the of efficacy of treatment of MDS pts with cyclosporine A (CSA) but they are limited to the group of pts with bone marrow hypoplasia. The aim of our study was to evaluate the efficacy of CSA treatment in MDS pts as first line or second line therapy. 48 pts with different forms of MDS were included in study. The group of first line CSA treatment included 30 pts, male-18/female-12, RA-3, RARS-1, RCMD-18, RAEB-7, RAEBt-1, 20-normal karyotype, 10-different abberations including: 5q−, 16q+, −7, 12q+, −Y, [11p+,7q−] and complex abb. Hypoplastic bone marrow was revealed in 15 pts, hyperplastic-8 pts, hypo/hyper-7 pts. Second line therapy group included 18 pts, male-9/female-9, RCMD-11, RARS-1, RAEB-5, RAEBt-1, normal karyotype-3, cytogenetic anomalies-13 (+8, 5q−,−7, +8 and complex abb.). Hypoplastic bone marrow was revealed in 12 pts, hyperplastic-4 pts, hypo/hyper-4 pts. The first line therapy consited of splenectomy in 8 pts, low doses of Ara-C-3, interferon-α-3, chemotherapy-2 and ATG-2 pts. CSA was applied at 5–10 mg/kg/day initially and then adjusted according to blood levels and toxicity. The maintenance dose was 1–3 mg/kg/day. Minimum time to response evaluation was one month. Complete response (CR) was defined as normal PB counts, BM aspirate; partial response-improvement of PB counts to 50% of normal and freedom from transfusions; stabilization-decrease of transfusion requirements and stabilization of PB counts for more then 1 month. Total response rate in first group was 60% (18 pts) with median follow up of 10 months (2–134). CR was estimated in 20% (6pts), median follow-up 72 months (44–134). 2 pts with CR are in clonal remission. 2 pts from response group developed acute leukemia (AL). 40% of pts showed no response.58% of pts without response developed RAEB or AL. 42% of pts were in stable disease and were treated with another modalities. The response rate in second group was 61% (11 pts) with median follow-up of 7 months (1–78). 22% (4 pts) achieved CR, median follow-up 60 months (43–78). 39% of pts showed no response. 71% from these pts (5) transformed to RAEB or AL. 2 pts remained in stable disease. In both groups response was registrated from 1 to 4 months from treatment initiation (median 3 months). CR was achieved in the majority of pts after 1 year of treatment. Response was achieved in 77% of pts with hypo/hyper and hypoplastic bone marrow and in 12% of pts with hyperplastic bone marrow. Overall survival was decreased in pts with more the 5% blasts in bone marrow (p=0,02 for 1st line group, p=0,075 for 2nd line group), and increased for pts with hypo and hypo/hyper bone marrow cellularity (p=0,002 for 1st line group). There was no impact of cytogenetics. We may conclude, that CSA demonstrates good efficacy in therapy of MDS pts, especially for pts with RA, RARS and RCMD with hypo and hypo/hypercellular bone marrow and reactive lymphoid nodules in bone marrow. It can be initiated as 1st or 2nd line therapy and should be continued at least for 3 months before evaluating of response.

Bortezomib Combined with VXLD Chemotherapy Is Highly Effective In Advanced B-Lineage Acute Lymphoblastic Leukemia Allowing Early Study Termination Due to Efficacy. A Therapeutic Advances in Childhood Leukemia (TACL) Consortium Phase II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 251-251
Author(s):  
Yoav H Messinger ◽  
Paul Gaynon ◽  
Richard Sposto ◽  
Jeannette van der Giessen ◽  
Elena Eckroth ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Phase Ii ◽  
Response Rate ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Platelet Recovery ◽  
Off Label ◽  
B Lineage

Abstract Abstract 251 Literature review and TACL experience support an expected less than 40% complete remission rate with variety of regimens in patients with ALL in second and subsequent relapse (Ko, J Clin Oncol 2010; 28: 648–654). We had shown that bortezomib might be safely combined with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin (VXLD) in the phase I portion of our study (Messinger, Pediatr Blood Cancer 2010;55:254–9). We now report the phase II expansion of that study. ALL patients who relapsed or were refractory after 2 or 3 regimens were treated with bortezomib 1.3 mg/m2/dose on days 1, 4, 8 and 11, combined with VXLD. Patients between ages 1 to 21 years old, with more than 25% bone marrow blasts, were eligible. One patient from the phase I cohort with these criteria was included in the phase II extension. In the phase II extension 22 patients were treated with this combination and all are included in analyses. All patients had relapsed or failed at least 2 prior regimens. Overall 14 achieved complete remission (CR; M1 marrow with ANC and platelet recovery and no extramedullary disease or circulating blasts) and 2 achieved CRp (CR with no platelet recovery) for total 73% remission rate (Table). This level of response exceeded the predefined criteria, allowing for early termination of the study. Three patients (14%) died from bacterial infections and two patients (9%) had no response (Table). One patient (4.5%) was not evaluable for response due to protocol violation, when additional therapy was administered before CR was confirmed with peripheral blood count recovery. B-Lineage ALL patients fared best, with 16/20 achieving CR + CRp (overall response rate 80%), whereas the two patients with T-cell ALL did not respond. Similarly, B-Lineage ALL had superior bone marrow response (M1 marrow): B-Lineage = 17/20 (85%) vs. T-cell = 0/2 (0%). Severe grade 3 or more peripheral neuropathy (PN) was seen in 2 (9%) patients, (one had prior vincristine PN). One patient has developed mucor invasive sinus and orbital infection, requiring halting therapy after day 14 but achieved CRp. After the 3 (14%) septic deaths, the use of vancomycin, levofloxacin and voriconazole or posaconazole prophylaxis in the last 6 patients has prevented further infectious mortality.ResponseAllBTn22202CR14 (64%)14 (70%)0CRp2 (9%)2 (10%)0Total Response16 (73%)16 (80%)0Deaths3 (14%)3 (15%)0SD/PD2 (9%)02 (100%)N/E1 (4.5%)1 (5%)0 In conclusion, the regimen of bortezomib + VXLD is exceptionally effective in multiple relapsed B-Lineage ALL with the highest response rate for any multiply relapsed ALL trial reported thus far. The use of prophylactic antibiotics may be effective in reducing mortality. Bortezomib with VXLD should be further evaluated in randomized fashion on frontline relapse and high-risk pediatric B-Lineage ALL clinical studies. Disclosures: Messinger: Genzyme: Consultancy. Off Label Use: Bortezomib (Velcade®) is approved for multiple myeloma and mantle cell lymphoma both B cell malignancies. We are describing use in relapsed B cell Acute Lymphoblastic Leukemia which is off label.”

Therapy of Acquired Aplastic Anemia (AA) with Rabbit Antithymocyte Globulin (rATG): A Retrospective Analysis by the Working Group on Non-Malignant Disorders of Hematopoiesis of the German Society of Hematology and Oncology (DGHO),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3434-3434
Author(s):  
Britta Höchsmann ◽  
Christiane Neher ◽  
Ulrich Germing ◽  
Janne Vehreschild ◽  
Juliane Eggermann ◽  
...  
Keyword(s):  
Data Collection ◽  
Aplastic Anemia ◽  
Research Funding ◽  
Response Rate ◽  
Retrospective Data ◽  
First Line ◽  
Off Label ◽  
Best Response ◽  
Retrospective Data Collection

Abstract Abstract 3434 Introduction: Several clinical trials established treatment with horse ATG (hATG) and cyclosporine A (CsA) as standard treatment of AA in patients (pts) who are not candidates for stem cell transplantation (SCT). In 2007 the hATG brand Lymphoglobulin® was withdrawn from the market. As the hATG brand ATGAM®, is not approved in Europe, hATG was replaced by rabbit ATG (rATG). Recently a large prospective randomized one-center study from NIH, USA comparing hATG ATGAM®/CsA and rATG Thymoglobulin®/CsA in untreated AA showed significantly lower response rates and survival with rATG. To obtain further information on rATG treatment in an unselected AA population, especially with a higher median of age and use of different rATG dosages we performed a retrospective data collection of first line rATG therapy on several centers. This shall reflect outcome after rATG in a real-world situation. Methods: Retrospective data collection and analysis of first line rATG treatment of AA after approval by Ethical Committee. Results: Up to now retrospective data of 64 pts from 18 centres in Germany were analysed. Characteristics of the pts: 30 male, 34 female; median age at time of therapy 54 years (6–80 years); 87.5% of pts had idiopathic AA. 51.6% of pts had severe AA, 32.8% very severe AA and 15.6% non-severe AA. Median granulocyte count was 0.3 G/l. 86% of the pts required red blood cell and 92% platelet transfusions. 56 of the evaluable pts received Thymoglobulin® and 5 pts Fresenius ATG S®. 52 of the 56 Thymoglobulin®-treated pts got this therapy in the years 2007–2011, i.e. not as deliberate primary choice of rATG but because hATG was no longer available. Median daily dose of Thymoglobulin® was 3.5 mg/kg (range from 2.5 – 3.75 mg/kg) for 5 days. 62 of 64 pts received additional immunosuppressive therapy with CsA and 19 of 64 pts received G-CSF. The median follow-up for surviving pts was 558.5 days (range, 78–3800 days). Response rates at time of best response of pts were CR in 10/58 pts (17%), PR in 18/58 pts (31%) and NR in 30/58 pts (52%) (only surviving patients with a minimum follow-up of 120 days were analyzed). Median interval to best response was 217 days. Response rate (PR+CR) was 16/33 (48.5%) in pts who received a Thymoglobulin® dose of > 3.5 –3.75 mg/kg/day versus only 4/14 (28.6%) group of 14 pts with a dose of > 2.5 to < 3.5 mg/kg/day (p=0.17; Fisher`s exact test). Relapses occurred in 3/28 responders and clonal evolution was observed in 3 pts (2 PNH, 1 MDS). Eighteen of 63 evaluable pts received allogenic SCT after ATG-therapy and were censored at the date of SCT. 23% of 44 pts without SCT died. In 6 of these 10 pts death was caused by infections. Other causes of death were bleeding, cardiac event, acute respiratory distress syndrome, adynamia. Overall probability of survival at 3 years was 75.8% (95% confidence interval (CI): 61.8 – 89.9%) and survival censored for SCT was 79.9% (CI: 66.0–92.8%). Survival was significantly better in responders (PR and CR) (94.1% at 3 years; CI: 82.9–100%) than in non-responders (58.0% at 3 years; CI 34.0 – 81.3%) (p=0.04; log-rank test). Adverse events were reported in 79.4% of 63 evaluable pts consisting of anaphylaxis/allergy in 27.3%, serum sickness in 12.7%, fever/chills in 34.5%, and bacterial/viral/fungal infections in 54.5% of pts. Conclusion: Response rate and survival after rATG+CsA in this retrospective analysis is lower than in historical controls (e.g. hATG+CsA treatment in previous controlled studies of the German AA Study Group and the EBMT AA Working Party; Frickhofen et al., Blood 2003; Tichelli et al., Blood 2011) and rate of (early) infections seem to be high. Our results are in accordance with recent reports from other groups. Additionally the results of this retrospective data analysis suggest a benefit for the patient group treated with a Thymoglobulin® dosage of > 3.5 –3.75 mg/kg/day compared to lower doses (< 3.5 mg/kg/day). There is growing evidence that best results in terms of response and survival are obtained by hATG-based immunosuppression. hATG can not be replaced by rATG without negative impact on patient outcome. There is need for action to achieve availability of hATG worldwide. If hATG is not available, treatment with rATG should be considered instead of no treatment or treatment with CsA alone since still about half of the patients respond to rATG. Disclosures: Höchsmann: Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: The use of the horse ATG ATGAM in Aplastic Anemia is off-label in Europe. At the moment no horse ATG with approval is available in Europe. Schrezenmeier:Genzyme: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Research Funding.

Fludarabine, Cytarabine, Daunoxome Plus Dasatinib Has High Efficacy with an Acceptable Toxicity Profile As Either Consolidation or Salvage Regimen in Adult Philadelphia Positive Acute Lymphoblastic Leukemia Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4908-4908 ◽  
Author(s):  
Giordana Pastori ◽  
Fabio Guolo ◽  
Daniela Guardo ◽  
Paola Minetto ◽  
Marino Clavio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
The Other ◽  
Consolidation Therapy ◽  
Toxicity Profile ◽  
Newly Diagnosed ◽  
Salvage Regimen ◽  
Minimal Residual

Abstract BACKGROUND AND AIMS The prognosis of Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients has improved since the introduction of tyrosine kinase inhibitors (TKI). The inclusion of TKIs in standard ALL protocols allows a great increase in complete molecular responses, but at the price of non negligible toxicities and high rates of toxic deaths. On the other and TKI monotherapy as induction treatment allows to rapidly achieve complete hematologic remission (CR) but only a minority of patients achieve a complete molecular response with high risk of relapse. On the other hand, In the last years we tested a combination of Fludarabine, Cytarabine, Daunoxome (FLAD) with or without TKIs (mainly Dasatinib) as salvage regimen in relapsed-refractory ALL, with acceptable toxicity and good efficacy. We decided to apply the same schedule in newly diagnosed Ph+ ALL as consolidation treatment after a two months TKI (Dasatinib) monotherapy induction on a minimal residual disease condition. MATERIALS AND METHODS FLAD regimen consisted with a three-days administration of Fludarabine 30 mg/sqm followed four hours later by Cytarabine 2000 mg/sqm and Daunoxome 100 mg/sqm. TKI were suspended during chemotherapy administration and were re-administrated starting from day 5. G-CSF was given to all patients from day 4 to complete hematological recovery. FLAD was administrated for up to two cycles; all patients with available donor proceeded to allogeneic bone marrow transplantation (allo-BMT) after FLAD. Minimal residual disease (MRD) was evaluated in all patients after each FLAD either by RQ-PCR for VDJ rearrangements, multicolor flow cytometry (MFC) and RQ-PCR for BCR/Abl. Ten Ph+ ALL have been treated with FLAD + TKIs from January 2008 to December 2014: six patients received FLAD as salvage regimen, two of them in post allo-BMT setting, whereas four patients were treated frontline, after hematological CR was obtained with Dasatinib + steroids induction. All frontline patients proceeded to allo-BMT after two FLAD. Median age for frontline patients was 50 years (range 29-58), median follow-up was 20 months. RESULTS As salvage regimen, 5/6 patients achieved hematological CR after FLAD, with three patients achieving also MFC MRD negativity and clearance of VDJ and BCR/Abl transcript. All patients who did not receive subsequent BMT relapsed, whereas of the two transplanted patients one is still in CR after a follow-up of 38 months. In the frontline setting, all patients received 70 days induction of Dasatinib + Steroids and achieved CR with complete hematological recovery. BCR/Abl transcript could be detected in all patients on BM samples on day 33 and on day 70 (Fig. 1), two patientshad MFC MRD positivity both on day 33 and on day 70, whereas two patients achieved MFC MRD negativity on day 33. FLAD was very well tolerated, with negligible non hematological toxicity, with a median duration of ANC <500 and PLT <20000 of 7 and 9 days, respectively, slightly higher in the second course. Median time between the beginning of first and second course was 35 days, whereas median time from second course to allo-BM was 44 days. Two patients achieved BCR/Abl negativity after first FLAD. All patients achieved molecular complete response after the second course (Fig. 1). No patient experienced relapse, whereas one patient died in CR on day +289 after allo-BMT due to myocardial viral infection. CONCLUSIONS FLAD has a very good efficacy in adult Ph+ ALL, with an acceptable toxicity profile. Deep responses have been observed in relapsed patients, and all newly diagnosed patients who received FLAD as consolidation regimen had achieved molecular CR before allo-BMT. Achieving complete hematological response with Dasatinib + steroids allowed us to safely administer two FLAD courses. Figure 1. BCR/abl on bone marrow samples at different timepoints for each of the four patients receiving FLAD as consolidation therapy Figure 1. BCR/abl on bone marrow samples at different timepoints for each of the four patients receiving FLAD as consolidation therapy Disclosures Off Label Use: Use of liposomal daunorubicin in the treatment of ALL.

EBV Related Lymphoproliferative Disorders Post Allogeneic Bone Marrow Transplantation for Haematological Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5480-5480
Author(s):  
A. Paisiou ◽  
C. M. Vadikolia ◽  
K. Stefanaki ◽  
E. Goussetis ◽  
I. Peristeri ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Allogeneic Bone Marrow Transplantation ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Haematological Malignancies ◽  
Hla Antigen ◽  
Post Transplant ◽  
Concurrent Infections

Abstract Background: Post transplant lymphoproliferative disorder (PTLD) is a heterogeneous complication of HSCT. It comprises a spectrum of pathogenetic mechanisms and clinical manifestations. It is mostly associated with EBV infection, either as a consequence of reactivation in the post transplant period or less frequently from primary infection. WHO classification defines four major histopathologic subtypes: 1. early plasmacytic hyperplasia and infectious mononucleosis (IM)-like 2. polymorphic lesions which may be polyclonal or focally monoclonal (P-PTLD) 3. monomorphic lesions that fulfill criteria for aggressive B- or T/NL-cell neoplasm (M-PTLD) 4. classic Hodgkin-type Lymphomas (CHL-PTLD). Indistinguishable categories, such as Hodgkin-like P-or M-PTLD might represent laborious diagnostic dilemmas. In literature, PTLD occurs in less than 1% of non T-cell-depleted grafts from matched siblings compared with as high as 25% in unrelated donor (VUD) recipients. There are several risk factors such as the type of conditioning and the use of ATG, the degree of immunosuppression and complications such as concurrent infections and GvHD. Objectives: To present our experience regarding the frequency, presentation and outcome of EBV related PTLD in a paediatric population of allo-HSCT recipients with haematological malignancies, to assess the risk factors and inquire into the heterogeneity in clinical presentation and outcome. Patients-Methods: From January 2004 until December 2014, 177 allo-HSCTs for myeloid and lymphoid malignancies were performed in patients aged 3 months to 19 years. PTLD was recorded in 15 (8 male) with median age of 13.24 yrs (range 5.0-17.9yrs). 11 patients had VUD, 4 patients had an haploidentical related donor and the grafts depleted of T-cells. 12 patients had peripheral blood and 3 had bone marrow as the source of HSCs. 4 were given a fully matched graft, 6 had 1 HLA antigen or allele mismatched donors, 1 patient had a 2 HLA antigen mismatched donor and 4 had 5/10 HLA matched haploidentical donors. All except for 2 patients were EBV IgG positive and the two seronegative patients had an EBV IgG positive donor. The conditioning regimens used were Busulfan or Treosulfan based in 11 patients with the addition of a combination of Cyclophosphamide, Fludarabine, Melphalan, VP16 and ATG. The latter was administered to all patients. GvHD prophylaxis consisted of Cyclosporin A and Methotrexate. Five patients (1 male) are alive and well with a median follow up of 43.1 months (range 8.3-69.2). Results: Neutrophil and platelet engraftment occurred at a median of 20 (range 14-24) and 21 days (range 14-48) respectively. Acute GvHD (stage II-IV) was recorded in 9 patients. Serial quantitative EBV-DNA/ml was employed routinely and the median day of confirmation of a rising level above 1.0x103/ml was day +58 post transplant. Median EBV copies at diagnosis were 2.3x104/ml(range 1.3x103/ml-2.15x105/ml). EBV positivity was immediately recorded post DLI in 3 patients and reactivation occurred post subsequent DLI. Immune reconstitution had not been achieved in any patient at the time of diagnosis. Median WBC count was 4.1x109/lt (1.04X109/lt - 8.78x109/lt) and all patients had absolute lymphopenia. 9 patients had documented other viral and/or bacterial infections. 2 patients developed M-PTLD, consistent unequivocally with DLBCL, 7 patients had P-PTLD and 6 patients had IM-like PTLD with plasmacytic hyperplasia only. All had anti-CD20, two patients had additional chemotherapy. Although responsive to EBV treatment, 3 died of primary disease recurrence while PTLD failed to regress in 7 patients who died of a multitude of complications. With a median follow up of 43,1 months (range 8.3-69.2), 5 patients (1 male) are alive and well. Conclusions: Nearly all HSCT recipients are EBV infected or will be infected eventually, yet only a fraction develop EBV driven PTLD. In our population the incidence was found to be 8.47%. PTLD exhibits a spectrum of features ranging from non specific and reactive to life threatening, indistinguishable from lymphoma. Administration of ATG, the type and extend of HLA mismatch, multiple sites of disease, immune suppression and concurrent infections heighten the risk of systemic manifestation. Rising EBV loads are strongly associated with impending PTLD, which can occur even with an overall modest viral load, thus requiring prompt recognition and early intervention. Disclosures No relevant conflicts of interest to declare.

FISH Analysis in Multiple Myeloma - a Retrospective Study from India

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5646-5646 ◽  
Author(s):  
Pratibha Dhiman ◽  
Shalini Goel ◽  
Priyanka Samal ◽  
Nitin Sood ◽  
Ritesh Sachdev ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Chromosomal Aberrations ◽  
Overall Response Rate ◽  
Response Rate ◽  
Indian Subcontinent ◽  
Fish Analysis ◽  
Interphase Fish

Abstract Introduction Multiple myeloma (MM) is a malignancy involving terminally differentiated plasma cells. It is characterized by a complex pattern of extensive genomic aberrations involving many chromosomes and it constitutes about 1% of all malignancies. Its exact incidence in India is not known. Based on data available from 6 population-based cancer registries in India (covering 0.3% of the population) its incidence varies from 0.3 to 1.9 per 100 000 for men and 0.4 to 1.3 per 100 000 for women. Among various prognostic markers in MM, cytogenetic abnormality detected by conventional cytogenetic and FISH studies are major factors deciding clinical outcome. Interphase FISH studies from various parts of the world have reported variable incidence (40 - 66%) of cytogenetic abberations. However, there is insufficient published data from Indian subcontinent addressing the frequency of chromosomal aberrations using interphase FISH in MM patients. Patients and Methods Sixty eight patients clinically diagnosed with multiple myeloma were studied. The retrospective period of recruitment was from Jan 2015 to June 2016. The diagnosis of MM was based on serum electrophoresis and immunofixation, bone marrow plasmacytosis, and end organ involvement. Interphase FISH analysis was performed on bone marrow samples using specific DNA probes- Del 13q14.3 (LSI D13S25) , t (4;14) ( Kreatech IgH/ FGFR3 DC-DF), t (11;14) (Zytovision directly labeled IgH/CCND1 DC-DF), t (14;16) (Kreatech IgH/ MAF DC-DF), Del 17p13.1( LSI TP53). A total of two hundred nuclei were enumerated for each FISH Panel probe and cut off for detection of deletion/ fusion signal in normal individuals was taken as 3%. An interim analysis of treatment protocols was also done. Results A total of 68 cases with MM were evaluated which included 55 males and 13 females. We report a median age of 58 years (37-86 years). Interphase FISH analysis was done in all patients. Out of sixty eight patients, 23 (33.82%) patients had one genetic abnormality. Results revealed that deletion 13q14.3 was the most frequent aberration. Out of 68 patients, 10 patients have 13q14 (14.7%) abnormality. This includes 70% males and 30% females. In addition absence of p53 at 17p13 was detected in 8/68 (11.8%) patients. Similarly 11q13 abnormality was observed in 3/68 (4.4%). IgH (14q32) aberrations were noted in 2/68 (2.94%) patients. Of which t(4;14) was detected in these patients, whereas none of them showed t(14;16). More than one chromosomal aberrations were present in 4 patients. Data for serum β2-microglobulin at the time of presentation could be evaluated in 52 patients only. Most of the patients 40(76.9%) belonged to ISS stage 3. From the available data, 4 patients with ISS stage 3 had high risk chromosomal abnormality whereas 3 patients with ISS stage 2 and none of the patient of ISS stage I disease had high risk chromosomal abnormality. A total of 40 patients received cyclophosphamide, bortezomib and dexamethasone as the primary treatment whereas 23 patients received Bortezomib, lenalidomide and dexamethasone based therapy. Post 2 cycles of cyclophosphamide based therapy showed an overall response rate (CR + VGPR) of 87.5% whereas in case of lenalidomide based therapy the overall response rate was 91%. Thirteen patients underwent autograft after durable response, out of which one had a clinical relapse within 3 months. Median survival can only be commented on further follow up. Conclusion In comparison to the west, the frequency of chromosomal aberrations are different and much less in India whereas the studies of median survival is comparable. An early age of presentation in Indian subcontinent is another issue to be addressed as we know that secondary mutations accumulate with increasing age, but a younger population presenting with same severity of disease needs exploration of additional abnormalities in India. Being a resource constraint country and non availability of molecular lab at every place, evaluation of each patient is difficult, however increasing awareness of the role of biology in the management of MM is inspiring the clinicians for detailed evaluation and close follow up of these patients. Certainly, larger trials are required to understand the biology of this disease in the country. Disclosures No relevant conflicts of interest to declare.

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