Response-Adjusted Transplantation in Primary Resistant and Relapsed Hodgkin Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 336-336 ◽  
Author(s):  
Kirsty Thomson ◽  
Irfan Kayani ◽  
Kirit M Ardeshna ◽  
Emma Morris ◽  
Rachael Hough ◽  
...  
Keyword(s):  
Residual Disease ◽  
Autologous Transplantation ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Unrelated Donor ◽  
First Line ◽  
Free Survival ◽  
Pet Ct ◽  
Donor Lymphocytes

Abstract Abstract 336 Therapeutic options for patients with primary resistant or relapsed Hodgkin Lymphoma (HL) have remained largely unchanged for the past 20 years, comprising salvage chemotherapy consolidated by autologous transplantation. Newer agents such as brentuximab vedotoxin may increase response rates, and are being evaluated in the maintenance setting after transplantation. For patients with chemosensitive disease, autologous transplantation confers 5yr progression-free-survival rates of 40–50%. Prognosis is worse in primary resistant or early relapsing disease (within 12 months of primary therapy). Functional imaging also provides prognostic information. Patients with metabolic complete response (mCR) prior to autograft have progression-free survival (PFS) rates in excess of 70% at 3–5yrs, whilst in those with chemosensitive disease (CR/PR) but residual metabolically active lesions these figures drop to 25–30%. The feasibility of performing allogeneic hematopoietic stem cell transplants in patients with HL using reduced intensity conditioning is well established. However, reduced non-relapse mortality rates have been associated with increased relapse, which is now the major cause of treatment failure. Registry data suggest the importance of dose intensity in determining relapse risk. Consideration of transplantation earlier in the disease pathway may improve the tolerability of increased dose intensity. We evaluated the feasibility of a response-adjusted transplantation strategy, based on assessment of disease status by FDG-PET-CT following salvage chemotherapy. Between November 2007 and December 2010 we treated 61 patients with primary refractory or relapsed HL at our institution. Patients were restaged following 1 line of salvage. Those in mCR were consolidated with a BEAM autograft, whilst non-progressive patients with <mCR were offered a BEAM-alemtuzumab allograft. Those with progressive or bulky residual disease were given further salvage until they demonstrated stable disease or better, at which point they were eligible for an allograft. Patients were monitored following the allograft for lineage-specific chimerism and restaged by PET-CT, and received dose-escalating donor-lymphocytes from 6 months post-transplant for mixed chimerism or residual disease/progression. 53/61 (87%) patients achieved sufficient response and were fit for high-dose therapy. 28 patients proceeded to autograft and 25 to allograft (8 related donor, 12 HLA-matched unrelated donor, and 5 HLA-mismatched unrelated donor). The majority had received ABVD as first-line therapy (n=48), and ESHAP as first-line salvage (n=48). 21 of those proceeding to allograft received mini-BEAM as additional salvage. The median number of lines of salvage was 2 (1–8) in the allograft cohort. 12/13 ‘late' relapses, 5/9 ‘early' relapses and 11/31 primary resistant cases received an autograft. The median age at transplant was 32 in both groups (range 18–66 for autograft vs 16–50 for allograft). Median follow-up is 2.5 vs 2.3 years respectively (range 0.5–3.6yrs in both). Outcomes in the autograft group were understandably good. NRM was 4%, and relapse incidence 11%. 3yr OS and PFS were 92% and 85% respectively. Outcomes following allografting in the higher risk cohort were also encouraging. All engrafted. NRM was 8% and relapse incidence only 16%, with all relapses occurring within 9 months of transplantation. 4 patients received donor-lymphocytes for relapse. All responded and 3 (all CR) are maintained. 3yr OS, PFS and ‘current' PFS are therefore 88%, 71% and 84% respectively. 4 patients developed grade II and 2 patients grade III acute graft-versus-host disease, and no patients were taking immune suppressants beyond 18 months after transplantation. The combined 3yr outcomes for all 53 transplanted patients are 90% OS, 78% PFS and 84% cPFS. In conclusion, the data demonstrate favorable survival outcomes for the entire cohort of primary resistant and relapsed patients. They illustrate that selected patients with primary resistant and early relapsed disease may do well following autografting, but more strikingly that those predicted to have poor outcomes based on functional imaging may have very favorable outcomes following alemtuzumab-based allografting with aggressive post-transplant immune modulation. The data now form the basis for 2 national UK studies. Disclosures: No relevant conflicts of interest to declare.

Potential elimination of multi-drug resistant cancer cells by targeted non-engrafting intentionally mismatched activated donor lymphocytes.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14007-e14007
Author(s):  
Shimon Slavin
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Malignant Cells ◽  
Free Survival ◽  
Donor Lymphocytes

e14007 Background: Immunotherapy by targeted autologous T cells, TIL or CAR-T, are considered most effective modalities for treatment of otherwise resistant cancer, yet cure is rarely achieved. In contrast, cure of resistant disease by donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation suggests that alloreactive lymphocytes represent a most effective approach for elimination of resistant malignant cells. The first patient relapsing following supra-lethal chemoradiotherapy is alive & well > 34 years. Using murine B cell leukemia (BCL1) and metastatic breast cancer (4T1) we proved that non-engrafting intentionally mismatched lymphocytes activated with IL-2 that were consistently rejected cured otherwise lethal cancer with no graft-vs-host disease (GVHD). Methods: We first applied graft-vs-tumor effects by non-engrafting Intentionally Mismatched Activated Killers (IMAK) following mild immunosuppressive conditioning to maximize homeostatic proliferation of activated T & NK cells. IMAK was first applied inpatients with multiple myeloma and lymphoma treated with donor lymphocytes pre-activated in vitro prior to infusion and for 5 days following infusion withlow dose IL-2.We next studied feasibility of Allogeneic Targeted Activated Cancer Killer cells (ATACK) using IL-2 activated haploidentical donor lymphocytes including T & NK cells targeted against antigens over-expressed on the surface of malignant cells: Her-2/neu, EGFR, VEGF and CD20 using commercially available Herceptin, Erbitux, Avastin or Rituximab, respectivelyin a pilot study involving 16 patients with advanced metastatic solid tumors. Results: Using IMAK donor lymphocytes were uniformly rejected and no patient developed GVHD. Disease-free survival > 20 years was documented in our first myeloma patient with plasmacytomas and in another relapsing after autologous SCTand in 2 patients with non-Hodgkin lymphoma. Longterm progression-free survival was reported in 5 of 31 patients with resistant solid tumors. Following ATACK transient mild toxicity was manageable in outpatient clinic and no GVHD developed. Conclusions: Using ATACK against minimal residual disease accomplishable by most cancer patients following conventional 1st line treatment may result in cure of otherwise resistant cancer while avoiding GVHD.

scholarly journals Case series: MRD negativity assessment using 11C-Acetate PET with 3-weekly daratumumab-based quadruplet induction in newly diagnosed multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110303
Author(s):  
Cheong Ngai ◽  
Shaji Kumar ◽  
Garrett Chi-lai Ho ◽  
Sirong Chen ◽  
Chor-sang Chim
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Case Series ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Positron Emission ◽  
Pet Ct ◽  
Subsequent Relapse

Complete response (CR) is an important favorable factor for survival in multiple myeloma (MM). However, CR patients continue to relapse, especially in the presence of minimal residual disease (MRD). Bone marrow (BM) MRD is predictive of progression-free survival (PFS) in MM. However, myeloma outside the BM aspiration site may result in subsequent relapse despite MRD-negativity. Therefore, positron emission tomography-computed tomography (PET-CT) based on F-fluorodeoxyglucose (FDG) is a complementary tool to monitor residual disease in MM. However, FDG may miss myeloma lesions that are not FDG-avid. On the other hand, 11C-Acetate (ACT) has been found to be a more sensitive and specific tracer than FDG in MM. Recently, the addition of daratumumab to bortezomib, thalidomide, dexamethasone (VTd) or bortezomib, lenalidomide, dexamethasone (VRd) backbone has been proven to improve outcomes. Herein, we report three newly-diagnosed MM patients achieving deep responses with imaging CR using ACT PET in addition to conventional immunofixation CR and MRD-negative CR after a 3-weekly daratumumab-based quadruplet induction regimen.

A new modified sunitinib schedule for metastatic renal cell cancer (mRCC): A pilot study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 471-471
Author(s):  
Sebastiano Buti ◽  
Maddalena Donini ◽  
Silvia Lazzarelli ◽  
Matteo Brighenti ◽  
Rodolfo Passalacqua
Keyword(s):  
Pilot Study ◽  
Meta Analysis ◽  
Cell Cancer ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
First Line ◽  
Treatment Delays ◽  
Free Survival ◽  
Dose Reductions ◽  
Modified Schedule

471 Background: Oral sunitinib administration at 50 mg daily given for 4 weeks followed by 2 weeks off treatment (4+2 schedule) is a standard first line for mRCC treatment. About 20% of patients had to discontinue treatment permanently and 50% of patients are forced to reduce the doses due to adverse events [Motzer RJ, J Clin Oncol. 2009]. A meta-analysis showed that increase exposure to sunitinib is associated with improved clinical outcome [Houk BE, Cancer Chemother Pharmacol. 2010]. Methods: This is a pilot study in which consecutive mRCC patients admitted to our hospital who had at least a grade 2 toxicity with sunitinib, were switched to a modified schedule maintaining the same dose-intensity of 4+2 schedule: starting on Monday, 1 tablet (50 mg) a day for 5 consecutive days a week for 5 weeks and 1 tablet per day on days 1, 3 and 5 in the sixth week (28 tablets in 6 weeks), until disease progression. Primary end points were toxicity changes assessment and schedule feasibility, secondary end point was overall progression free survival (PFS). Results: Eight nephrectomized patient were enrolled: 6 males; median age 61; 37% good, 50% intermediate and 13% poor MSKCC risk; 3 patient pretreated; 6 clear cell histologies, 1 papillary and 1 undifferentiated histotypes. Median time from start therapy to switch was 7.4 months (range 1.4-16.1). Treatment delays and dose reductions were reduced from 50% to 25% and from 37% to 12% of patients respectively. The table shows the toxicity changes: there were no new toxicities. PFS was 16.3 months (CI 95% 5.6-23.4). Conclusions: This new modified schedule requires and deserves further studies. [Table: see text]

scholarly journals Amrubicin Monotherapy for Patients with Platinum-Refractory Gastroenteropancreatic Neuroendocrine Carcinoma

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Takayuki Ando ◽  
Ayumu Hosokawa ◽  
Hiroki Yoshita ◽  
Akira Ueda ◽  
Shinya Kajiura ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
First Line ◽  
Ki 67 ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Platinum Refractory ◽  
Grade 3

Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, the role of salvage chemotherapy remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC.Methods. Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2007 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively.Results. Eight males and two females (median age, 67 years (range, 52–78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n=7, 70%), cisplatin plus etoposide (n=2, 20%), and carboplatin plus etoposide (n=1, 10%) before amrubicin therapy. Median progression-free survival and overall survival after amrubicin therapy were 2.6 and 5.0 months, respectively. Two patients had partial response (20% response rate), and their PFS were 6.2 months and 6.3 months, respectively. Furthermore, NEC with response for amrubicin had characteristics with a high Ki-67 index and receipt of prior chemotherapy with cisplatin and irinotecan. Grade 3-4 neutropenia and anemia were observed in four and five patients, respectively.Conclusion. Amrubicin monotherapy appears to be potentially active and well-tolerated for platinum-refractory gastroenteropancreatic NEC.

scholarly journals Progression Free Survival (PFS) Analysis of Daratumumab (Dara), Cyclophosphamide, Thalidomide and Dexamethasone: A Quadruplet Intensified Treatment for Transplant Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3943-3943
Author(s):  
Edvan De Queiroz Crusoe ◽  
Joanna Leal ◽  
Marco Aurelio Salvino ◽  
Larissa Ferreira Lucas ◽  
Juliana Andrade Santos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cell ◽  
Chromosomal Abnormalities ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Free Survival ◽  
Post Transplant ◽  
Investigational Agent ◽  
Pet Ct ◽  
One Year

Abstract Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)-(CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth and duration of the response. We hypothesized that Dara and CTd combination could be safe and allow deeper activity as an alternative protocol. Aims: The aims of this analysis were to evaluate Progression Free Survival (PFS) of Dara-CTd treatment and minimal residual disease (MRD) after one year of Dara maintenance. Primary endpoint of the study was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT). Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance &gt; 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. The MRD was evaluated by next-generation flow (NGF) based and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method. All pts received antiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Data cut-off was June 15, 2021. Results: The first pts was enrolled in November 2018. A total of 24 pts were included, the median age being 60 (range 37- 67 years), 23 (92%) were non-white, 5 (21%) had an R-ISS = 1, 12 (54%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Six (25%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 20 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and six (30%) pts needed plerixafor use. By ITT analysis after a median follow up of 20 months the PFS at 12 and 18 months was 86%. No PFS difference was observed between different subgroups. Regarding response rates, after the end of induction (cycle 4), 19 (90%) of the pts obtained &gt; PR and 8 (38%) obtained &gt;VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained &gt; VGPR as best response, 13 (76%) obtained MRD negativity by NGF and 10 (58%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Six pts completed one year of maintenance and five of them (83%) still MRD negativity by NGF. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Two pts have discontinued treatment due to progression - 1 before ASCT e 1 during maintenance. The most common adverse events (AEs) grades 3 and 4 were neutropenia (n = 12), infusion reaction (n = 7), neuropathy (n = 6), lymphopenia (n = 4), infection (n = 3), hypertension (n = 1) and rash (n = 1). Summary/Conclusion: The Daratumumab - CTd protocol is an active regimen capable of producing deep and sustainable responses and improve the PFS of NDMM TE pts with a favorable safety profile. Clinical trial information: NCT03792620. Disclosures De Queiroz Crusoe: Janssen: Research Funding. Hungria: Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria; Abbvie: Honoraria; Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel .

Pilot Evaluation of the Value of FDG PET-CT after One and Two Cycles of Salvage Chemotherapy in Relapsed/Refractory Aggressive Non-Hodgkin’s and Hodgkin’s Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4951-4951
Author(s):  
Andrew Hodson ◽  
Tara Barwick ◽  
Brigitta Marson ◽  
Nick Maisey ◽  
Kavita Raj ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Pet Ct ◽  
Risk Of Relapse

Abstract Introduction The currently accepted standard of care for patients with relapse/refractory NHL is dose escalation and consolidation with Stem Cell Transplantation. The ability to predict those patients who may benefit or not from this approach would be beneficial. Whole-body Positron Emission Tomography using 18F-fluorodeoxyglucose (FDG) is now recognised to have predictive ability in those patients at high risk of relapse and shortened overall survival in De novo High grade lymphoma. In the salvage setting it is unknown whether the appearance of PET scan after 1 cycle of salvage treatment may predict similarly for outcome post transplant and whether early scanning is indicated before cycle 2 salvage chemotherapy. Aim: The aim of this study is to assess whether the PET-CT after one cycle or two cycles of dose escalation was predictive of outcome in patients with relapse/refractory NHL. Methods: We collected the data prospectively of all patients with relapsed or refractory aggressive NHL or HD treated in our institution over a 2 year period who were considered suitable for salvage therapy followed by Stem Cell Transplantation. We identified 14 male and 10 female patients with a mean age of 44 years (range 24–66). 12 patients had disease refractory to first line treatment and 12 patients had relapsed disease with a median interval from completion of treatment to relapse of 20 months (range 2–60). All patients were initially treated with DHAP as salvage therapy.22/24 patients proceeded to a stem cell transplant. 16/22 had an autologous transplant conditioned with BEAM and 6/22 had allogeneic transplants.FDG PET- CT scans were performed (all positive) prior to salvage chemotherapy and then assessed after 1 cycle of salvage chemotherapy and then after the second cycle using a 5 point visual scoring system as follows: CMR - no uptake at disease sites, MRU1 – visually uptake below level of mediastinum, MRU2 – visually between mediastinum and liver Stable/persistent metabolically active disease and Progressive disease (either new lesions or increased uptake in the same sites. Results FDG-PET Data was collected from 24 patients (14 male and 10 female) and read by two independent observers. The patients had the distribution shown in table: Visual response criteria Appearance PET 1 : Patient Numbers Appearance PET 2 : Patient Numbers CMR 1 6 MRU1 0 2 MRU2 1 3 Stable/persistent 16 5 Progressive 6 8 The median progression free survival of the patients with progression after one cycle of chemotherapy was 1.5 months with 3/6 deaths. Progression on PET1 was seen only in refractory cases pre salvage and was associated with a significant risk of relapse (p=0.014). The median progression free survival of the patients with stable disease after one cycle was 9.5 months. After two cycles of chemotherapy the median progression free survival of patients with CMR/MRU1/MRU2 was 9 months, compared with stable disease of 8 months and progressive disease 6 months. Conclusions: Patients with progressive disease on PET after one cycle of chemotherapy have a poor outcome with 50% early deaths and would be candidates for targeted/experimental therapies. Longer follow up will be required to assess the significance of stable or persistent disease on PET after one cycle and two cycles of salvage chemotherapy.

Targeting non-engrafting IL-2 activated intentionally mismatched donor lymphocytes with monoclonal or bispecific antibodies for treatment of otherwise incurable cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15033-e15033
Author(s):  
Shimon Slavin
Keyword(s):  
Multiple Myeloma ◽  
Solid Tumors ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Unrelated Donor ◽  
Incurable Cancer ◽  
Killer Cells ◽  
Free Survival ◽  
Donor Lymphocytes

e15033 Background: Cure of certain resistant cancers by donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation (SCT) suggests that alloreactive lymphocytes can eliminate otherwise resistant cancer. First patient with resistant relapse following supra-lethal chemoradiotherapy treated with DLI is alive & well > 34 years; > 400 patients with hematological malignancies confirmed DLI efficacy for prevention & treatment of relapse. Using murine leukemia (BCL1) & metastatic breast cancer (4T1), IL-2 activated mismatched lymphocytes with no prior SCT eliminated otherwise lethal minimal residual disease (MRD). Using anti-EpCAM x anti-CD3 bispecific antibody (BSA) lethal melanoma was eliminated, also resulted in long-lasting immunity against lethal tumor challenge. Graft-vs-host disease (GVHD) was prevented by consistent rejection of mismatched lymphocytes. Accordingly, our goal was to develop effective immunotherapy of cancer using non-engrafting intentionally mismatched Allogeneic Targeted Activated Cancer Killer cells (ATACK) using relevant monoclonal antibodies (MoAb) or BSA. Methods: Patients with multiple myeloma & lymphoma and advanced solid tumors were treated with haploidentical or unrelated donor lymphocytes pre-activated 5 days with IL-2, following non-myeloablative conditioning with endoxan or fludarabine and IL-2 injection x5 days for in vivo lymphocyte activation. ATACK with no MoAb was investigated in 40 patients with different cancers. Safety of ATACK with MoAb was investigated in 16 patients with resistant NHL, metastatic breast, lung & colorectal cancer, using commercial MoAbs against CD20, Her-2, EGFR or VEGF, respectively, or using anti-EpCAM BSA. Results: Protocols were well-tolerated with mild transient toxicity following ATACK and BSA. No patient developed GVHD. Disease-free survival > 15 years was documented in 2/2 patient with multiple myeloma and 2/2 patients with lymphoma. Longterm progression-free survival was observed in 5/31 evaluable patients with advanced metastatic solid tumors treated with no MoAbs. Minor toxicity in targeted ATACK recipients was manageable in outpatient clinic. Conclusions: Intentionally mismatched IL-2 activated killer cells guided by MoAbs or BSA represents a promissing approach for treatment, possibly even cure, of cancer patients with MRD while avoiding GVHD.

Minimal Residual Disease (MRD) Status in FCR-Treated CLL Patients at the End of Treatment Influences Progression Free Survival (PFS), Results of the Ctrial-IE (ICORG) 07-01/ CLL Ireland Study, with Mutational Analysis Providing Additional Insight

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3237-3237
Author(s):  
Niamh Appleby ◽  
Fiona M Quinn ◽  
David O'Brien ◽  
Smyth Liam ◽  
Johanna Kelly ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Research Funding ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
First Line ◽  
Free Survival ◽  
Minimal Residual ◽  
First Line Treatment

Abstract Fludarabine, cyclophosphamide and rituximab (FCR) therapy results in a complete remission (CR) rate of 72% and a median progression free survival (PFS) of 80 months in non-del (17P) CLL1. Achieving an MRD negative (MRD-ve) CR after completing therapy is an early surrogate marker for overall survival (OS) and PFS2. Specific genetic CLL subtypes determined by fluorescent in-situ hybridisation (FISH) analysis, immunoglobulin mutation IgVH, NOTCH1 and SF3B1 status determine response to chemotherapy3,4. We completed a multi-centre prospective study between 2008 and 2012, with a median follow up of 62.6 months using MRD status to determine length of therapy. Patients who achieved an MRD-veCR after 4 courses of FCR received no further therapy and the remaining patients completed 6 cycles of FCR. MRD status was tracked 6 monthly in patients who became MRD-veuntil MRD was detected. The genetic subtype was also analysed but did not influence treatment. Fifty-two patients {35M;17F, median age 61years (range 37-73)} were enrolled. Forty-six patients completed the MRD assessment after 4 cycles. Eleven patients discontinued assigned FCR therapy for the following reasons: prolonged cytopenia (4); non-compliance (1); autoimmune haemolytic anaemia (2); renal impairment (1); pleural effusion (1); not recorded (2). Eighteen (34.6%) patients achieved an MRD-veCR after 4 cycles and a further11 after 6cycles resulting in 29/52 (55.8%) MRD-veCRs in total. The median PFS was 72.3 months (95% Confidence Interval 61.3-84.1 months) and the median OS has not been reached. Patients who attained an MRD-veversusMRD+vestatus had a prolonged PFS (81.1 vs 46.2 months, p<0.0002). No difference in PFS was observed between patients reaching an MRD-veCR after 4 versus 6 cycles (median PFS81.1 vs 84.1 months,p=0.29). FISH results were available for 48 patients; del(13q) in 16/48 (33%), del(11q) in 15/48 (31%) no abnormality in 12/48 (25%), trisomy 12 in 4 (8%) and other abnormality in 1 patient. The IgVH status was unfavourable in 34/52 (65%), SF3B1 mutations were detected in 5/51 (9.8%) and NOTCH1 mutations in 10/52(19.2%) patients respectively, comparable to published studies of first-line treatment in CLL3,4. The median PFS for patients with good risk IgVH was not reached. Del(11q) did not impact on PFS (median PFS 66.5 vs 78.9 months, p=0.7301). SF3B1 and NOTCH1 mutated patients had a shortened PFS (median PFS 38.4 vs 71.1 months, p=0.038 and median PFS 62.4 vs 82.2 months p=0.0302, respectively). In conclusion abbreviated FCR therapy is effective for patients achieving MRD-veremission after 4 cycles. SF3B1 and NOTCH1 mutated patients had a short PFS and may benefit from alternative first-line treatment. This finding emphasizes the role mutational profiling will play in optimising and personalising therapy in CLL in the future. Reference: Tam C, O'Brien S, WierdaW, et al. “Long-term results of the fludarabine, cyclophosphamide and rituximab regimen as initial therapy of chronic lymphocytic leukemia” Blood 2008 Aug 15;112(4):975-80 Böttcher S, Ritgen M, Fischer K, et al. "Minimal Residual Disease Quantification is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial" J Clin Onc 2012 Mar 20; 30(9):980-8. StilgenbauerS,SchnaiterA,PaschkaP, et al. "Gene mutations and treatment outcome in chronic lymphocyticleukemia: results from the CLL8 trial" Blood 2014 May 22;123(21):3247-54 Chiaretti S, Marinelli M, Del Giudice I, et al."NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukaemia undergoing first-line treatment: correlation with biological parameters and response to treatment"LeukLymphoma 2014 Dec; 55(12):2785-92 Figure 1 Patient outcomes by MRD status in ICORG 07-01 Trial Figure 1. Patient outcomes by MRD status in ICORG 07-01 Trial Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Crotty: BMS, Takeda, Novartis, Janssen, Roche: Honoraria. O'Dwyer:Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

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