scholarly journals Characteristics of Patients (pts) Who Relapse and Die of Multiple Myeloma (MM) within One Year Post Frontline Autologous Stem Cell Transplant (ASCT) in the Novel Agent Era: An Ultra-High Risk Population

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3440-3440 ◽  
Author(s):  
Hatem Alahwal ◽  
Heather J. Sutherland ◽  
Shruthi Ganeshappa Kodad ◽  
Stephen H. Nantel ◽  
Yasser Abou Mourad ◽  
...  
Keyword(s):  
High Risk ◽  
Control Group ◽  
Case Group ◽  
First Year ◽  
Advanced Stage ◽  
Second Line ◽  
Disease Relapse ◽  
Second Line Therapy ◽  
Line Therapy ◽  
One Year

Abstract Introduction: MM remains incurable but therapeutic advances has resulted in improved overall survival (OS) particularly for younger pts who are eligible for ASCT. Regardless OS improvements have been heterogeneous and it is well known that relapse within one year of ASCT is an independent negative prognostic factor. A particularly worse subgroup is pts who relapse and die of MM within a year of ASCT. There is limited data describing this subgroup of pts, the risk factors associated with their early relapse post ASCT and characteristics at relapse. Objective: Describe patient and disease related characteristics among MM pts who underwent ASCT and died of relapsed MM within the first year post ASCT in the era of novel agents. Methods: Pts were identified from the Leukemia/BMT Program of B.C. database, underwent ASCT between January 1st 2007 and July 31st 2016 and died of MM related causes within 365 days post ASCT. During this time period bortezomib (BORT) and lenalidomide (LEN) were available as second line therapy and BORT was available as induction pre-transplant for defined circumstances including high risk cytogenetics. Out of 752 ASCTs, 702 were performed as a part of initial therapy. The remaining ASCTs were performed as salvage or were the second of planned tandem ASCTs. Among the remaining 702 pts 37(5.3%) died within the first 365 days post ASCT. Of the 37 pts, 32 died from MM and related causes, 2 died of TRM from ASCT and 3 died from other causes not related to MM or ASCT. The 32 pts (4.6% of the total) who died of MM and related causes were matched with 64 controls (2:1 ratio) who were selected randomly from the remaining patient cohort and matched for age, gender, and year of transplantation. Results: There was no difference in Age at diagnosis (Median: case 61 VS control 60, P= .97) or gender (Male case 40.6% VS control 35.9%, P= .66). There was no significant difference in the prevalence of anemia, renal dysfunction, or hypercalcemia between both groups at diagnosis (table). Pts who died within the first year of ASCT had a more advanced stage at diagnosis compared to the control group (ISS Stage III: 53.1% vs 18.8%, P= .003). BORT based induction therapy was used in 84.4% of the cases compared to 53.1% in the control group, P= .001. The majority of pts in both groups had partial response or better to frontline therapy (Cases: 81.2% VS Controls 79.7%, P= .5). Only 9.4% of cases and 4.7% of controls had evidence of disease progression at the time of ASCT. High risk cytogenetics (t(4;14), t(14;16), or del 17p) were significantly more prevalent among pts who died within the first year post ASCT compared to the control (58.82% vs 31.67%, P= .009). There was no difference in the monoclonal protein subtype between the cases and controls, P= .55. The median time from ACST to disease relapse was 118 days (40-319) for the case group compared to 511 (107-1958) in the control group. Within the case group, 19 (59.3%) received LEN based therapy as second line therapy and 9 (28.1%) received BORT based therapy. Three patients (9.37%) were not candidates for any further therapy due to acute illness (2 sepsis, 1 subdural hemorrhage) related to fulminant MM relapse and one patient (3.1%) decided not to proceed with therapy due to functional decline. Overall, 17 pts (53.1%) received both BORT and LEN during the disease course, 12 (37.5%) received BORT only, 2 (6.25%) received LEN only and one received neither (3.1%). At the time of disease relapse, 9 (28.1%) had Hb level <85 g/l, 1 (3.1%) ANC<1000/mm3, 9 (28.1%) Plt <50/mm3, 9 (28.1%) GFR <20 ml/min, and 20 (62.5%) had at least one abnormal value (Hb, ANC, Plt, or Cr) and were not candidates for inclusion to clinical trials. Median OS (months) was Case 7.3 vs Control 63.8, P<.001. Conclusion: Approximately 5% of pts with MM who are ASCT eligible will die of MM within the first year post transplant. High risk cytogenetics (t(4;14), t(14;16), or del 17p) and advanced stage disease (ISS III) are risk factors for early mortality post ASCT for MM pts. These patient who relapse early typically have fulminant relapse with hematological and biochemical parameters outside of the range which would allow them to be enrolled on clinical trials and/or results in challenging standard of care management. Even in the era of novel agents, such pts do particularly poorly and represent a true unmet need in the treatment of MM. Further studies to understand the biology of their MM is required for identifying more potent therapeutic targets and protocols. Disclosures No relevant conflicts of interest to declare.

scholarly journals Modified Rio Score with Platform Therapy Predicts Treatment Success with Fingolimod and Natalizumab in Relapsing-Remitting Multiple Sclerosis Patients

2021 ◽  
Vol 10 (9) ◽  
pp. 1830
Author(s):  
Anna Jamroz-Wiśniewska ◽  
Radosław Zajdel ◽  
Agnieszka Słowik ◽  
Monika Marona ◽  
Marcin Wnuk ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Treatment Success ◽  
Prospective Trial ◽  
Poor Response ◽  
Response To Treatment ◽  
First Year ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Multiple Sclerosis Patients

Background: Reliable markers of disease outcomes in multiple sclerosis (MS) would help to predict the response to treatment in patients treated with high efficacy drugs. No evidence of disease activity (NEDA) has become a treatment goal whereas the modified Rio score (MRS) predicts future suboptimal responders to treatment. The aim of our study was to identify factors that would predict poor response to treatment with natalizumab and fingolimod. Methods: In the multicenter prospective trial, 336 subjects were enrolled, initiating therapy with natalizumab (n = 135) or fingolimod (n = 201). Data on relapse rate, the expanded disability status scale, and MRI results were collected, and MRS was estimated. Results: NEDA-3 after the first year of therapy was 73.9% for natalizumab and 54.8% for fingolimod (p < 0.0001). Patients with MRS = 0 in the last year on platform therapy had the best NEDA-3 (71%) and patients with MRS = 3 had the worst NEDA-3 (41%) in the first year of treatment with the second-line therapy. Conclusion: We conclude that switching to the second-line therapy should occur earlier to enable better results for patients treated with natalizumab or fingolimod. The outcome on both drugs is better with better neurological conditions and lower MRS of the patient on the platform therapy.

Treatment with Homoharringtonine and Cytarabine in Patients with High Risk Acute Myelogenous Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4555-4555
Author(s):  
Naibai Chang ◽  
Jianping Wei ◽  
Shengming Zhao ◽  
Hui Liu ◽  
Yun Fan ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Free Survival ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Second Line ◽  
Second Line Therapy ◽  
Conventional Dose ◽  
Line Therapy ◽  
Acute Myelogenous

Abstract Objective: To evaluate response of homoharringtonine in patients with high risk AML or as a second-line therapy in patients with AML refractory to anthracycline based chemotherapy. Patients and methods: From Jan 1998-Jan 2006, there were 66 patients enrolled in this regimen. Male:female=40:26. Median age was 47 (17–69). There were 48 newly diagnosed AML, 5 relapsed AML and 13 secondary AML (secondary to MDS) in this group. Among these patients, there were 40 patients untreated previously — 20 patients had unfavourable chromasomal abmormalities, 10 patients had pgp positive, 10 patients had normal chromasome but high CD34 expression on leukemic cells. The remaining 26 patients were previously treated with daunorubincin or mitoxantrane combined with cytarabine at least two cycles and failed to achieve response. Homoharringtonine was given at dose of 4mg/m2/d(2.5mg/m2/d for age≥60 years) intraveniously for 7 days. Cytarabine was given at dose of 100mg/m2/d at same time. The therapy was repeated every 21 days.Post remission therapy was divided into two cohot —same regimen maintainance in 20 cases and cytarabine 1g/m2/d q12h for 4 days at least 4 cycles in 20 cases. Results: 40/66 patients achieved complete remission. 3/66 achieved partial remission. In patients refactory to anthracycline based regimen, the CR rate was 57.7%(15/26). In previously untreated high risk AML patients,the CR rate was 62.5%(25/40). Median disease free survival were 4.25 months (2–30) in cohot 1 and 18 months (12–47) in cohot 2 (P&lt;0.05). CD95(APO-1/Fas) was tested by flow cytometry during treatment. APO-1/Fas (CD95) increased from (9.56±5.58)% to (25.64±0.70)% after induction chemotherapy. Main toxicities were marrow suppression and infection. There were 7 early deaths, 5 patients died of cerebral hemorrage and 2 cardiovascular events. Conclusions: Homoharringtonine is effective in patients with high risk AML. It is also a choice of second line therapy in patients refractory to anthracycline based chemotherapy. Intensive post remission therapy is superior to conventional dose maintainance therapy in high risk AML. One of the ways for homoharringtonine to induce leukemic cell apoptosis is probably through Fas pathway.

Salvage Therapies in Patients with High-Risk Relapse After Fludarabine, Cyclophosphamide, Rituximab (FCR) for Chronic Lymphocytic Leukemia: The French CLL Intergroup Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1796-1796
Author(s):  
Luc-Matthieu Fornecker ◽  
Therese Aurran-Schleinitz ◽  
Anne-Sophie Michallet ◽  
Bruno Cazin ◽  
Jehan Dupuis ◽  
...  
Keyword(s):  
High Risk ◽  
Second Line ◽  
Complex Karyotype ◽  
First Line ◽  
Second Line Therapy ◽  
High Risk Patients ◽  
First Line Therapy ◽  
Line Therapy ◽  
Ultra High Risk ◽  
Risk Patients

Abstract Abstract 1796 Introduction: FCR chemoimmunotherapy is recommended as first line therapy for fit cll patients. Since the 2007 EBMT guidelines based on the previously published trials using FCR, the definition of high risk CLL has evolved, to include biologic parameters (TP53 disruption by deletion/mutation, high b2-microglobulin level, IgVH unmutated, complex karyotype), refractoriness (progression during fluda-based regimen or within 6mo of completion), and also remission duration (high risk if PFS after FCR <24mo, ultra-high risk if TTNT <24–36mo with TP53 del/mut). However, few data are available regarding the characteristiscs, response rate and outcome of CLL patients treated in second line after FCR first line. Patients and methods: In this multicentric retrospective study, we collected data from 117 patients who relapsed after FCR first line therapy and received second-line therapy (according to NCI2008 guidelines). Results: At the time of initial FCR therapy: patients characteristics were as follows: Binet B/C 87.2%, unmutated IgVH 52.2%, del11q 25.6% (n=30/81 with FISH available), del17p 6.8% (n=8/87 with FISH available), bulk>5cm 22%, complex karyotype 21% (n=12/57 with karyotype available). FCR yielded 93% ORR, with 66% clinical CR, 27% PR, and 7% failed to respond. Median PFS and TTNT were 27mo and 32.5mo, respectively. At the time of relapse: patients characteristics were as follows: del11q 16.4% (n=19/65 with FISH available), del17p 19% (n=22/77), bulk>5cm 26%, complex karyotype 44% (n=24/54 with karyotype available). According to FCR remission duration, 11.1% of patients were considered as truly FCR-refractory, 47% had PFS<24mo, 34.2% had TTNT<24mo. TTNT<24mo after FCR was correlated to age>65y, del17p (20% vs 0%) and complex karyotype (38% vs11%), but not with gender, IgVH status, del11q, or bulk>5cm. Based on FCR-refractoriness, or TTNT<24mo and/or del17p, 53 patients were considered as ultra-high risk (45.3%). Various regimen were used for second-line treatment after FCR: R-bendamustine (n=47, 40.2%), alemtuzumab-based therapy (single agent or with chemo/dexa, n=22, 18.8%), R-CHOP (n=15, 12.8%), FCR (n=14, 12%), and other miscellaneous regimens (as follows: R-alkylator (n=6, 5.1%), R-DHAP (n=4, 3.4%), R-methylprednisolone (n=3, 2.6%), or investigational drugs (n=6, 5.1%)). Thus, 74.3% of patients received a second course including rituximab-based chemotherapy. Overall response rate was 78.4%, with 13.8% clinical CR, 64.6% PR, and 21.6% failure/stable disease. 14 pts (12%) underwent stem cell transplantations, 8 had maintenance therapy ongoing (ofatumumab, alemtuzumab, or lenalidomide). With regards to factors defining high-risk relapse, distribution of salvage therapies was as follows: As expected, a second course of FCR was seldom used in high-risk patients. Among ultra-high risk patients, 30.3% received R-benda, 11.3% Alem-based Rx, 32% R-CHOP and 18% the miscellaneous regimens described above. After second-line therapy, median PFS was 12 months, median TTNT was 14mo, and median OS was 36mo (20 deaths). On univariate analysis, complex karyotype (p=0.04) but not del17p (p=0.1), PFS<24mo (p=0.028) and TTNT<24mo (p=0.04) correlated with OS. Regarding treatment, OS was significantly improved in R-bendamustine-treated patients, as compared to alem-based or CHOP regimen (p=0.01). Most importantly, patients who received an allogeneic transplant benefited from significantly prolonged OS (at 4y, 70% vs 40%, p=0.03). Of note, only one patient treated with R-benda received allotransplant. Conclusions: This study shows that there are no consensus for second line therapy after FCR. Second line trials after FCR therapy are warranted. Definition of high-risk subsets of patients at relapse after FCR is of upmost importance in the management of CLL, to compare second-line strategies. Our data suggest that R-bendamustine is an efficient regimen even in high-risk patients (complex karyotype, PFS<24mo, TTNT<24mo). These data are important since this immunochemotherapy is now used as the backbone for combination with new compounds (ibrutinib, GS1101, GDC-199). Disclosures: Aurran-Schleinitz: Roche: Honoraria. Leblond:Roche: Advisory Board Other, Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen-Cilag: Honoraria.

Phase I/II study of MKC-1 and pemetrexed (PEM) as second-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19005-e19005
Author(s):  
N. H. Hanna ◽  
D. Estes ◽  
J. Arnott ◽  
S. Marcotte ◽  
A. Hannah ◽  
...  
Keyword(s):  
Phase 1 ◽  
Combined Treatment ◽  
Single Agent ◽  
Second Line ◽  
Phase 2 ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Best Response ◽  
Grade 3 ◽  
One Year

e19005 Background: MKC-1 is a novel oral cell cycle inhibitor with preclinical activity against NSCLC cell lines including multi-drug resistant lines, and single agent activity in NSCLC pts. Binding targets of MKC-1 include microtubules, members of the importin-β family and AKT-mTOR. This phase 1/2 study evaluated MKC-1 in combination with PEM as second-line therapy in pts with advanced NSCLC. Methods: Eligible pts had NSCLC previously treated with one regimen for metastatic disease or disease progression within one year following adjuvant and neoadjuvant therapy. Phase 1 dose escalation used 3+3 design. Phase 2 pts were treated with MKC-1 at 75 mg/m2 given p.o. BID for 14 days along with PEM at 500 mg/m2 given i.v. on day 1 of each 21 day cycle. Following 4 cycles of combined treatment, single agent MKC-1 was continued as maintenance therapy. An interim analysis after 17 pts in phase 2 would allow accrual to continue provided one response was confirmed. Results: 27 pts were enrolled (8 in phase 1 and 19 in phase 2). Median age/PS for phase 2 is 64/1 and 89% had adenocarcinoma. Total # of treatment cycles to date for phase 2 pts is 95, with a median of 4 cycles. Of the 19 phase 2 pts, 18 were evaluable for tumor response. The best response was confirmed PR, noted in 3 pts. 5 additional pts (4 confirmed) had minor responses (>10% but <30% shrinkage). One additional pt continues on study with stable disease for >18 months. In phase 2 (n=19), all grade toxicities were anorexia (59%), fatigue (63%), nausea (58%), and dyspnea (48%). Grade 3/4 toxicities included fatigue (26%); neutropenia (22%); dyspnea, anorexia, AST and ALT elevation (11% each); nausea and constipation (5% each). 7 pts had at least one dose reduction of both PEM and MKC-1 and 3 additional pts had only MKC-1 reduced. Median PFS was 86 days with two pts continuing on study (treated for 530+ days and 140+ days, respectively). Conclusions: The phase 2 dose of MKC-1 (75 mg/m2 BID) and PEM (500 mg/m2) has been defined. The combination is well tolerated with 17% of patients achieving a confirmed PR thus far. A decision to proceed with additional accrual in this single arm study versus initiating a randomized phase 2 study of this combination is pending. [Table: see text]

Combination therapy of low-dose gemcitabine and paclitaxel in every 4 weeks for patients with platinum-resistant urothelial cancer whose performance status is 2 or 3.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 462-462
Author(s):  
Tomohiro Matsuo ◽  
Yasuyoshi Miyata ◽  
Yuji Sagara ◽  
Kojiro Ohba ◽  
Hideki Sakai
Keyword(s):  
Combination Therapy ◽  
Urothelial Cancer ◽  
Low Dose ◽  
Performance Status ◽  
Control Group ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Grade 3 ◽  
Experimental Group

462 Background: Platinum-based regimens are standard therapy for advanced urothelial cancer (UC). However, second-line chemotherapy is still not established. Therefore, best supportive care is often selected in patients with poor performance status (PS). In our hospital, combination therapy of low-dose gemcitabine and paclitaxel every 4 weeks is administered as second-line therapy for platinum-resistant patients with PS 2 or 3. We investigated the quality of life (QoL) and safety of our regimen in these patients. Methods: Forty-two advanced UC patients were treated with gemcitabine (700 mg/m2 on day 1) and paclitaxel (70 mg/m2 on day 1) every 4 weeks (experimental group). The QoL was evaluated using the short-form survey (SF)-36, and the data were collected on the day before the first cycle was started and 8 weeks after starting the therapy. In addition, survival analysis was performed between these patients and 30 patients who received no second-line therapy (control group). Results: In experimental group, one patient showed grade 3 anemia after the treatment. However, this patient also had severe hematuria before staring of the therapy. No patient had severe adverse events (grade 3 and higher) because of this therapy. The QoL score decreased after the therapy; however, the difference was not significant. With regard to efficacy, partial response was found in two patients, and the mean/SD survival period of the experimental group was 9.2/7.2 months. This period was significantly (P < 0.01) longer than that in the control group (5.8/2.4 months). In addition, 13 (31.0%) and 6 patients (14.3%) survived over 12 and 18 months, respectively. Conclusions: Combined therapy of low-dose gemcitabine and paclitaxel every 4 weeks was well tolerated, and the patient’s QoL was maintained after treatment. Some patients showed relatively long survival periods. We suggest that this treatment regimen is worthy of consideration as second-line therapy for patients with advanced UC with PS 2 or 3.

scholarly journals Efficacy and Toxicity of Gemcitabine Plus Docetaxel Combination as a Second Line Therapy for Patients with Advanced Stage Soft Tissue Sarcoma

2012 ◽  
Vol 13 (2) ◽  
pp. 463-467 ◽  
Author(s):  
Kaya Ali Osman ◽  
Buyukberber Suleyman ◽  
Ozkan Metin ◽  
Alkis Necati ◽  
Sevinc Alper ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Advanced Stage ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy

Pentamidine: A Review

1991 ◽  
Vol 12 (6) ◽  
pp. 375-382 ◽  
Author(s):  
Michael W. Scheld ◽  
Brian Wispelwey ◽  
Richard D. Pearson
Keyword(s):  
High Risk ◽  
Clinical Results ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Aerosolized Pentamidine ◽  
Pentamidine Isethionate ◽  
Low Toxicity ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

With the advent of the acquired immunodeficiency syndrome (AIDS), the therapeutic importance of pentamidine isethionate has increased greatly. This review summarizes the pharmacology, clinical experience in the treatment of Pneumocystis carinii pneumonia, and toxicity of pentamidine. Data are conflicting as to whether pentamidine is more or less effective than trimethoprim-sulfamethoxazole (TMP-SX) for the treatment of P carinii pneumonia in individuals with AIDS, but due to its toxicity and expense, it is considered as second-line therapy for P carinii pneumonia by many authorities. Hypoglycemia has been encountered in up to 27%, and nephrotoxicity in 25%, of treatment courses with pentamidine. In an attempt to circumvent the toxicities associated with parenteral administration, aerosolized delivery has been evaluated for both therapy and prevention of P carinii pneumonia. Aerosolized pentamidine, on the basis of early clinical results, convenience, and low toxicity, is being used extensively to prevent P carinii pneumonia in individuals at high risk. Relapses occur, however, and pneumothorax may be more common in those using this form of prophylaxis. Aerosolized pentamidine should not be used as sole therapy for acute P carinii pneumonia.

The open, multicenters, double-arms, randomized, parallel controlled clinical trial of lobaplatin or gemcitabine combined with docetaxel as second-line therapy for advanced osteosarcoma-the effectiveness and safety analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e22506-e22506
Author(s):  
Yuanjue Sun ◽  
Yang Yao ◽  
Zhengdong Cai ◽  
Xiuchun Yu ◽  
Sujia Wu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Statistical Difference ◽  
Objective Response ◽  
Survival Rates ◽  
Control Group ◽  
Controlled Clinical Trial ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy

e22506 Background: to study the progression free survival (PFS), objective response rate (ORR), overall survival (OS) and safety of lobaplatin or gemcitabine combined with docetaxel as second-line therapy for advanced osteosarcoma. Methods: the NO. of clinical trial was HNCA001,a total of 15 cases were enrolled into experiment group adopted lobaplatin combined with docetaxel,and 14 into control group received gemcitabine combined with docetaxel.The trial concluded screening, treatment and follow-up periods.21 dyas as one treatment period,they got drugs at the first day,and were evaluated the effects per two periods, treated at most 6 periods. Results: The baseline characteristics of two groups were no ststistical differences(diastolic blood pressure excluded) (P > 0.05).The PFS rates of 2,4 and 6 periods in experiment group were 87.50%、87.50% and 70.00%,83.33%,27.78% and 0 in control group,middle PFS more than 12 months in experiment group and 3.20 months in control group;while there was no statistical difference of PFS rates(χ2= 2.42,P = 0.1194).The survival rates of 2,4 and 6 periods in experiment group were 100.00%,83.33% and 83.33%,83.33%,83.33% and 0 in control group,the middle OS more than 12 months in the two groups, there was no statistical difference of survival rates (χ2= 0.65,P = 0.4196).The ORR was 6.67% in experiment group and 0 in control group(P = 1.0000).There were no adverse events occurring in the two groups. Conclusions: There is negative results of the trial,most reason may be the samples are greatly less;the next step is samples expanded and follow-up extended for the priority of lobaplatin or gemcitabine combined with docetaxel as second-Line therapy for advanced osteosarcoma. Clinical trial information: NCT02099396.

Life after Fludarabine, Cyclophosphamide, & Rituximab (FCR) - the Clinical Outcome of Patients with Chronic Lymphocytic Leukemia Who Receive Salvage Treatment after Frontline FCR.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2090-2090 ◽  
Author(s):  
Constantine S. Tam ◽  
William G. Wierda ◽  
Susan O’Brien ◽  
Susan Lerner ◽  
Issa F Khouri ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Salvage Treatment ◽  
Refractory Disease ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy

Abstract The FCR regimen is the most active treatment program in CLL, with 72% of frontline patients achieving a complete remission (CR) lasting a median of 7 years. However, most patients are not cured and will eventually relapse with CLL. In order to evaluate how these patients should be subsequently managed, we analyzed our institutional experience with 300 patients treated with frontline FCR (Blood 112:975). After a median follow-up of 6 years, 116 patients (39%) had failed FCR therapy with 13 primary refractory disease and 103 relapses from partial remission (PR), nodular PR (nPR) or CR. Compared with patients in ongoing remission, relapsed/refractory patients had more adverse baseline characteristics including a greater proportion with performance status ≥ 1 (71% vs 53% p=0.002), elevated β2m (54% vs 36% p=0.002), white cell count ≥ 150 x 10^9/L (25% vs 12% p=0.003), unmutated IgVH (81% vs 44% p&lt;0.001) and ZAP-70 positivity (78% vs 49% p&lt;0.001). The aim of the current analysis was to determine the duration of survival (OS) following second-line therapy in 97 patients who had completed salvage treatment. The median follow-up was 32 (range 3 – 69) months, and the median OS (mOS) was 32 months. Characteristics associated with favorable OS were: (1) previous best response to FCR of nPR/CR lasting ≥ 18 months (mOS 47 months, vs 13 months for primary refractory disease, PR or nPR/CR lasting &lt;18 months p=0.002); (2) β2m &lt; 3.0 mg/L (mOS not reached, vs 17 months p=0.0003) and (3) platelets ≥ 100x10^9/L (mOS 47 months, vs 15 months p=0.004). Poor risk cytogenetic abnormalities were common at FCR failure: among 38 assessable patients, 7 (18%) had 17p- and 18 (47%) had 11q- by conventional karyotyping and/or FISH. Although patients with 17p- or 11q- had an inferior survival, this survival disadvantage was confined entirely to those who also had an elevated β2m ≥ 3.0 mg/L. Surprisingly, patients relapsing after durable FCR remissions (≥ 5 years) and patients with slowly progressive relapse (time to salvage ≥ 12 months after FCR failure) had similar OS as their more adverse counterparts (p=0.76 and 0.86 respectively). A prognostic model comprising β2m and platelet count effectively divided patients into low, intermediate and high risk categories with mOS of &gt;45, 32 and 13 months respectively (p&lt;0.0001). Patients received treatment chosen at the discretion of individual treating physicians and the CR rate of second-line therapy were: FCR (n=30), 17%; rituximab (n=25), 4%; alemtuzumab ± rituximab (n=16), 31%; FCR & alemtuzumab (CFAR, n=9), 56%; lymphoma-type chemotherapy (n=5), 0%; other treatment (n=12), 0%. The CR rate for CFAR was significantly higher than that of FCR (p=0.03), although the median remission duration (30 vs 20 months) and OS (44 vs 32 months) were similar (p=0.87 and 0.51 respectively). None of the regimens showed a significant survival benefit. Allogeneic stem cell transplantation (SCT) was performed in 27 (28%) patients at a median of 15 months after first salvage. Patients receiving SCT had a significantly superior OS than those who did not undergo SCT (not reached vs 30 months, p=0.03). Of the 14 patients surviving for more than four years, 11 (79%) had undergone a SCT. Patients who fail FCR therapy had high risk disease features including elevated β2m, unmutated IgVH and ZAP-70 positivity, and most had adverse cytogenetic findings at relapse. Results of salvage therapy in this group were poor with a median survival of less than three years. The majority of long-term survivors had received allogeneic stem cell transplantation.

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