Combination of Rituximab, Bortezomib and Hyper-Fractionated Cyclophosphamide (RBC) in “True” Elderly Patients with Advanced Mantle Cell Lympoma.

Abstract Mantle-cell lymphoma (MCL) is recognized as a distinct clinico-pathologic entity, accounting for 3–10% of all non-Hodgkin’s lymphomas, with median overall survival not exceeding 3–4 years. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The neoplastic cells are characterized as CD20+ CD5+ CD23−, with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. The current, most diffused regimens for the treatment of MCL include either R-CHOP or R-HyperCVAD, followed by autologous stem cell transplantation or observation, depending on the patient’s eligibility. However, considering that MCL is frequently diagnosed in elderly subjects with relevant co-morbidities, high dose chemotherapy or the use of drugs with potential cardiotoxicity, such as anthracyclines, may result not feasible in a significant proportion of patients. In this setting, recent data suggest that the proteasome inhibitor bortezomib is well tolerated and has significant single-agent activity in patients with MCL. Thus, we evaluated safety and efficacy of the RBC regimen, a 21-day cycle, anthracycline-free combination of rituximab (375 mg/m(2) on day 1), bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11) and hyper-fractionated cyclophosphamide (600 mg/m(2)/d given as a double, three-hour infusion on days 1–3) in “true” (≥ 75 year-old) elderly patients with advanced MCL. Diagnosis was made according to standard histological, phenotypic and molecular criteria. The results of an early analysis on feasibility in the first six patients enrolled (3 male, 3 female) are reported here. Mean age was 79.8 years (range 75–84). All patients had stage IV disease, evidencing extranodal localizations (n. 2) or marrow/leukemic involvement (n. 4). IPI score was 2 in three patients, 3 in two patients and 4 in one patient. Three patients received RBC as first line therapy, the others were treated at relapse after (R)-CHOP- like regimens. Hematological toxicities consisted in grade 1 (n. 2) and grade 2 (n. 1) thrombocytopenia, while one patient experienced grade 3 neutropenia, requiring G-CSF support. No extra-hematological toxicities higher than grade 1 were observed. Full doses of RBC were constantly administered. One patient, who presented with a WBC count > 200.000/μl, died during the first cycle due to progressive disease; another patient showed an initial response in extranodal sites and then progressed before the fourth planned cycle. The remaining four patients received six cycles: one patient achieved a partial response and three obtained a complete response, one of whom showing a molecular remission using PCR for t(11;14) bcl-1/IgH determination. All responders (66.6%) maintain their remission phase 7–10 months after the start of RBC treatment. Although very preliminary, these results indicate that RBC regimen is feasible, well tolerated and may be effective (including the possibility to obtain molecular response) in very elderly patients with advanced MCL. Larger and more mature data will be presented at the Meeting.

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Current Treatment Approaches for Mantle-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2005.55.017 ◽

2005 ◽

Vol 23 (26) ◽

pp. 6409-6414 ◽

Cited By ~ 109

Author(s):

Thomas E. Witzig

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Single Agent ◽

Stage Iv ◽

Current Treatment ◽

New Agents ◽

Male Predominance ◽

Response To Chemotherapy ◽

Mantle Cell ◽

Stage Iv Disease

Mantle-cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of B-cell non-Hodgkin's lymphoma. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The cells are characterized as CD20+ CD5+ CD23− with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. Response to chemotherapy usually results in a tumor response but unmaintained remissions are short and the median survival is 3 to 4 years. The treatment approach to newly diagnosed patients with MCL depends on the patient's eligibility for stem cell transplantation (SCT). Those who are eligible are usually treated with either rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by SCT or rituximab-HyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate) followed by observation. The purine nucleoside analogues also have activity as single agents and with rituximab. Unfortunately none of these approaches can definitively cure patients with MCL, and new agents are needed. Recent studies in patients with relapsed MCL have shown substantial antitumor activity of single-agent bortezomib, single-agent temsirolimus, and the combination of thalidomide and rituximab. Studies integrating these novel agents earlier in the disease course or in combination with each other will hopefully produce more durable responses with less toxicity.

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Promising Results of Ibrutinib in Three Patients with Secondary Central Nervous System Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.3105.3105 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3105-3105

Author(s):

Sophie Bernard ◽

Lauriane Goldwirt ◽

Sandy Amorim ◽

Pauline Brice ◽

Josette Briere ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

Standard Dose ◽

Single Agent ◽

Stage Iv ◽

Complete Response ◽

High Dose ◽

Rituximab Maintenance ◽

Mantle Cell ◽

Meningeal Dissemination

Abstract Introduction. Risk of CNS dissemination in mantle cell lymphoma (MCL) is a rare and secondary event that occurs during the course of the disease. Prognosis from time of CNS involvement diagnosis is poor despite high-dose metabolite chemotherapy. New drugs are emerging in MCL treatment. The oral inhibitor of Bruton's tyrosine kinase (BTK), Ibrutinib (Pharmacylics, Sunnyvale, CA), has demonstrated unprecedented single agent overall response rate in relapsed or refractory MCL. Efficacy of Ibrutinib in CNS relapse is not known. Patients and methods. In 2014, three patients with MCL presented with a refractory secondary CNS dissemination at our institution. Patient 1, a 61 years old man, was first diagnosed in November 2009 with MCL, stage IV with a nodal, bone marrow and colon dissemination. MIPI score was evaluated as 5.5 (low risk). Patient received R-DHAX (rituximab, dexamethasone, aracytine, oxaliplatine) x 4 cycles followed by a high-dose R-BEAM therapy plus autologous stem cell transplantation (ASCT) (LYMA trial). First CNS relapse occurred in November 2012 as a right retro-ocular nodule and optic nerve infiltration. Patient was treated with R-IVAM, (rituximab, aracytine, ifosfamide, vepeside, high-dose methotrexate) x 6 cycles, with a complete response. He relapsed in December 2013 during rituximab maintenance, and was treated with CHOP-procarbazine x 3 cycles with a progression of the retro-ocular nodule and a peripheral nodal dissemination. Ibrutinib single agent was started in April 2014 at standard dose (560 mg/day). Patient 2, a 77 years old woman, was first diagnosed in February 2013 with MCL, stage IV disease with a nodal, splenic, blood, and bone marrow dissemination. MIPI score was 7.67 (high risk). Six cycles of R-CHOP followed by Rituximab maintenance was given. Relapse occurred during the Rituximab maintenance as an isolated meningeal dissemination. Patient received 6 cycles of R-DHA with a complete response. One month later, she presented an early relapse with meningeal dissemination and a left retro-orbital nodule. Ibrutinib single agent was started in May 2014 at standard dose. Patient 3, a 62 years old man, was first diagnosed in January 2011 with MCL stage IV with a splenic, blood and nodal dissemination. MIPI score was evaluated at 5.8 (intermediate risk). The patient had a splenectomy in March 2011. He relapsed in July 2013 with a blood, liver and nodal infiltration. The patient was treated with R-DHAX x 4 cycles followed by a high-dose R-BEAM therapy plus ASCT. He relapsed in July 2014 with a transverse myelitis. Ibrutinib single agent was started at standard dose. In parallel we studied plasmatic and CSF pharmacokinetic of Ibrutinib in one patient. Results. All patients were alive, respectively at 4 and 3 months and two weeks. CNS response of patient 1 by CT showed a tumor reduction of 81% with a complete CNS response on TEP at 4 months (Fig 2A and 2B). A complete response of peripheral nodal involvement was also observed. Patient 2 was evaluated with CSF study and CNS MRI. We observed an important decrease of CSF involvement (from 900 cells/mL to 100 cells/mL) as early as day 15 (Fig 1), and a response of the retro-orbital lesion (-23%). However an increase of lymphoma cells in CSF was observed at day 64 and was associated with 88 % decrease in Ibrutinib plasma exposure. At the same time, Ibrutinib CSF concentration measured at Tmax remained stable from day 8 to day 36, ranging from 1 to 3 ng/mL, with a CSF concentration/plasmatic concentration ratio of 0,019. Patient 3 rapidly improve his clinical exam with a recuperation of motor deficit and sensitive level at day 8. MRI was evaluated at day 8 of Ibrutinib and showed a spectacular response with a 69% decrease of myelitis trasverse and a regression of contrast enhancement (Fig 2C). Conclusion. This is the first report of efficacy of Ibrutinib in CNS lymphoma dissemination. We observed in these 3 cases an objective response and a pharmacodynamy proof of Ibrutinb CSF diffusion. Hypotheses for progression in patient 2 are 1/ a variability of Ibrutinib exposure; or 2/ the apparition of a C481S mutation of BTK. This observation is pivotal as CNS dissemination of other lymphoma subtypes, such as diffuse large B-cell lymphoma, or indolent lymphomas (follicular or marginal zone lymphoma) are all associated with poor prognosis. Given Ibrutinib upfront may eradicate this risk of dissemination and has to be prospectively evaluated. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Amorim: Oncoethix SA: Research Funding. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria. Thieblemont:Oncoethix SA: Research Funding.

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Lenalidomide, Bendamustine, and Rituximab As First-Line Therapy for Patients > 65 Years with Mantle Cell Lymphoma: Results From the Phase I Portion of the Nordic Lymphoma Group MCL4 (LENA-BERIT) Trial

Blood ◽

10.1182/blood.v118.21.2700.2700 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2700-2700 ◽

Cited By ~ 4

Author(s):

Mats Jerkeman ◽

Arne Kolstad ◽

Anna Laurell ◽

Riikka Räty ◽

Kirsten Grønbæk ◽

...

Keyword(s):

Elderly Patients ◽

Phase I ◽

Mantle Cell Lymphoma ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

High Dose Chemotherapy ◽

High Dose ◽

First Line ◽

Mantle Cell

Abstract Abstract 2700 Background: Mantle cell lymphoma is a disease of the elderly, with a median age of 70 years. Younger patients may be treated with potentially curative treatment including high dose chemotherapy. For elderly patients, however, no standard therapy has been defined. In a randomized comparison between R-CHOP and R-bendamustine (R-B) by the German StiL Group, R-B was associated with less toxicity and improved outcomes, making R-B a preferable first-line treatment option. Lenalidomide (LEN) is another active agent in MCL, with a response rate of 53% as a single agent in relapsed/refractory MCL. In the current trial, we investigate if the addition of lenalidomide to R-B may enhance efficacy, with manageable toxicity, for the older population of MCL patients. Methods: In phase I, the MTD of LEN was to be determined, starting with 5 mg/day increasing up to 25 mg/day in a sequential dose escalation using a 3+3 design. LEN, bendamustine and rituximab are given in 6 cycles/28 days. LEN D1-21, B 90 mg/m2 D1-2 and R 375 mg/m2 D1. The maintenance phase consists of LEN 25 mg/day, D1-21, for 7 cycles. Eligibility criteria are age > 65 years or ≤ 65 years, unable to tolerate high dose chemotherapy, with stage II-IV untreated mantle cell lymphoma. Results: The trial was commenced in October 2009.The phase I portion initially recruited 12 pts according to the original protocol design in 3 cohorts with LEN dose from 5–15 mg d 1–21. Median age was 72.5 years, range 66–85. MIPI high risk n=8, intermediate risk n=4. Response after 6 cycles: CR/CRu n=9/10, PR n=1/10 (ORR 100%). Molecular remission in BM: 5/9 pts. Toxicity was more profound than expected, mostly during cycle 1 (SAE n=9, AE Grade III/IV n=14). Notable was a high incidence of cutaneous and allergic AE. No patients could receive more than 10 cycles, median 6.5. A dose limiting toxicity (DLT) was noted at the dose of 15 mg. This led to a modification of the phase I protocol: Cohort A: No LEN in cycle 1, cycles 2–6: 10 mg LEN days 1–14. During maintenance, cycles 7–8: LEN 10 mg days 1–21, cycles 9–13: LEN 15 mg days 1–21. Cohort B: Same as Cohort A, but reducing B to 70 mg/m2 in cycles 2–6. Cohort C: as Cohort B, but reducing LEN to 5 mg days 1–14 cycles 2–6. In Cohort A, 2 of 6 patients experienced a DLT. Evaluation of Cohort B (6 pts) is ongoing. Conclusions: The addition of LEN to the R-B regimen leads to increased toxicity in elderly patients with MCL. Early data indicate a high response rate. Disclosures: No relevant conflicts of interest to declare.

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Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin’s Lymphomas

Advances in Hematology ◽

10.1155/2012/523842 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Marco Gunnellini ◽

Lorenzo Falchi

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Single Agent ◽

Response Rates ◽

Prognostic Scores ◽

Cell Transplant ◽

Survival Times ◽

Phase Ii Studies ◽

Mantle Cell ◽

Hodgkin's Lymphomas

Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.

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Treatment of relapsed non-Hodgkin's lymphomas with dexamethasone, high-dose cytarabine, and cisplatin before marrow transplantation.

Journal of Clinical Oncology ◽

10.1200/jco.1991.9.3.423 ◽

1991 ◽

Vol 9 (3) ◽

pp. 423-431 ◽

Cited By ~ 61

Author(s):

O W Press ◽

R Livingston ◽

J Mortimer ◽

C Collins ◽

F Appelbaum

Keyword(s):

Marrow Transplantation ◽

Disease Free Survival ◽

Stage Iv ◽

Large Cell ◽

High Dose ◽

Primary Therapy ◽

Bulky Disease ◽

Free Survival ◽

Hodgkin's Lymphomas ◽

Disease Free

Combination chemotherapy is capable of curing many patients with newly diagnosed intermediate- and high-grade non-Hodgkin's lymphomas (NHL), but treatment of relapsed NHL remains problematic. Bone marrow transplantation (BMT) offers the best chance for disease-free survival, but interim chemotherapy is often necessary while awaiting BMT, especially for patients with bulky disease. We report here 39 patients (median age, 44 years) who failed primary therapy with doxorubicin-based regimens and subsequently were treated with one to six cycles of dexamethasone, 40 mg intravenous (IV) every day on days 1 to 4, cisplatin 100 mg/m2 by continuous infusion on day 1, and cytarabine 2 g/m2 IV every 12 hours x two doses on day 2 (DHAP) before the planned BMT. Histologies included 16 diffuse large-cell, six diffuse mixed, five diffuse small-cleaved, four lymphoblastic, and eight other. Twenty-eight patients had stage IV disease, 13 had B symptoms, and 20 had an elevated lactate dehydrogenase (LDH). Patients had been treated with a median of three previous chemotherapy regimens. Sixty-one percent of patients had high tumor burdens according to the MD Anderson criteria. Objective responses to DHAP were seen in 26 patients (67%) including nine complete responses (CRs) (23%) and 17 partial responses (PRs) (44%), and responses lasted a median of 7.5 months. Myelosuppression was the major toxicity, but there were no treatment-related deaths. To date, 17 patients have undergone subsequent BMT with a projected 3-year disease-free survival of 15%. We conclude that the DHAP regimen is effective short-term salvage therapy for relapsed NHL patients, but the long-term prognosis of multiply relapsed patients remains poor.

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Follicular lymphoma: prognostic factors for response and survival.

Journal of Clinical Oncology ◽

10.1200/jco.1986.4.10.1470 ◽

1986 ◽

Vol 4 (10) ◽

pp. 1470-1480 ◽

Cited By ~ 313

Author(s):

C J Gallagher ◽

W M Gregory ◽

A E Jones ◽

A G Stansfeld ◽

M A Richards ◽

...

Keyword(s):

Follicular Lymphoma ◽

Poor Prognosis ◽

Single Agent ◽

Stage Iv ◽

Poor Response ◽

Stage I ◽

Stage Ii ◽

Response To Treatment ◽

Stage Iv Disease ◽

Short Courses

One hundred forty-eight patients with newly diagnosed follicular lymphoma were treated over a 12-year period. Twenty-two patients received radiotherapy for stage I and II disease, followed by adjuvant chemotherapy in 14 patients. One hundred thirteen were treated at presentation with short courses of chemotherapy, most often with single-agent chlorambucil for bulky stage II and stages III and IV disease. Thirteen patients were managed expectantly until there was evidence of disease progression. The median survival was 9 years. Patients treated with radiotherapy for stage I and II disease had an 83% relapse-free survival, but those with bulky stage II or stages III and IV disease treated with chemotherapy pursued a remitting and relapsing course with a 70% response rate at initial and subsequent retreatments, but a median duration of remission of 4 years in stage III and 1 year in stage IV disease (P = .041). Patients were observed in relapse and retreatment was administered as appropriate, once every 33 months on average. Poor prognosis patients could be identified by a combination of the presentation characteristics: B symptoms, hepatosplenomegaly, anemia, and abnormal liver function. These factors predicted a poor response to treatment and correlated with a short survival. Histologic subgroups were not associated with differences in survival, but transformation to a diffuse high-grade lymphoma was observed in 23 of the 72 patients (32%) at risk, with a median follow-up of 6 years and 6 months, and was associated with a very poor prognosis. The present treatment strategy has proved successful for most patients with localized disease and those older patients with indolent small volume disseminated follicular lymphoma. New approaches are being investigated for the younger poor prognosis patients.

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Use of anti-EGFR agents among elderly patients with metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.657 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 657-657 ◽

Cited By ~ 1

Author(s):

Ashley James D'Silva ◽

Efrat Dotan ◽

Dwight D. Kloth ◽

Andrew Beck ◽

Steven J. Cohen ◽

...

Keyword(s):

Overall Survival ◽

Combination Therapy ◽

Elderly Patients ◽

Treatment Initiation ◽

Single Agent ◽

Stage Iv ◽

Cancer Center ◽

Hematologic Toxicity ◽

Kras Status ◽

Grade 3

657 Background: Limited data are available regarding the tolerance of older mCRC patients to anti-EGFR therapy. To evaluate the treatment patterns and tolerability of cetuximab/panitumumab in this patient population, we conducted a retrospective review of elderly patients treated with these agents at Fox Chase Cancer Center between 2004-2010. Methods: Patients ≥ age 65 with mCRC treated with cetuximab/panitumumab were included in the analysis. Patient demographics, disease characteristics, treatment drugs and duration, KRAS status and overall survival were recorded. Toxicity evaluation included review of common hematologic and non-hematologic toxicities seen with these agents. Results: 118 patients were included; 100 received cetuximab and 18 received panitumumab therapy. The majority of patients were male (59.3%) with colon cancer (82.2%) and stage IV disease at presentation (50.8%). The median age at treatment initiation was 73 yrs (range: 65-90). Median overall survival was 510 days, and the median time on treatment 73 days. Most patients were treated prior to the incorporation of routine KRAS testing thus, KRAS status was available for 35 patients (29.7%) with 14.2% KRAS mutant tumors. 66% of cetuximab and 45% of panitumumab treatments were given in combination with another agent. The overall incidence of any grade 3/4 non-hematologic toxicity was 36% (34% for single agent; 37.8% for combination therapy). Common grade 3/4 non-heme toxicities were: hypomagnesemia-16.9%, diarrhea-10.2%, and rash-9.3%. Diarrhea and hypomagnesemia were more common among patients receiving combination therapy. The overall incidence of any grade 3/4 hematologic toxicity was 15.2% (6.8% for single agent ; 20.3% for combination therapy). Anemia was the most common heme toxicity in both single and combination therapy. Advanced age at treatment initiation was associated with higher incidence of single agent therapy (p=0.0005, ANOVA statistics). Conclusions: Our data demonstrate that elderly patients with mCRC tolerate anti-EGFR therapy, with toxicity rates similar to those reported in large clinical trials with younger patient populations. Older mCRC patients can safely receive anti-EGFR treatment as part of their therapy.

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NRG1 fusion-positive lung cancers: Clinicopathologic profile and treatment outcomes from a global multicenter registry.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9081 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9081-9081 ◽

Cited By ~ 6

Author(s):

Michaël Duruisseaux ◽

Stephen V. Liu ◽

Ji-Youn Han ◽

Valerie Gounant ◽

Jin-Yuan Shih ◽

...

Keyword(s):

Single Agent ◽

Treatment Strategies ◽

Stage Iv ◽

Large Cell ◽

Disease Stage ◽

Lung Cancers ◽

Best Response ◽

Pathologic Features ◽

Platinum Based Chemotherapy ◽

Stage Iv Disease

9081 Background: NRG1 fusions are potentially actionable driver events enriched in NSCLCs, particularly invasive mucinous adenocarcinomas (IMAs). These fusions activate HER3/HER2, supporting the therapeutic use of HER3 and/or HER2 inhibitors, but optimal treatment strategies remain unclear. Methods: A global, multicenter network of thoracic oncologists (6 countries, 13 institutions) identified patients with pathologically confirmed NRG1 fusion-positive NSCLCs. Anonymized clinical/pathologic features and clinical outcomes were collected retrospectively. Best response to systemic therapy was determined (RECIST v1.1). PFS was calculated (Kaplan-Meier). Results: 80 NRG1 fusion-positive NSCLCs were identified. RNA-based sequencing identified 66% (n = 53/80), DNA-based sequencing 18% (n = 14/80), and FISH 16% (n = 13/80) of cases. The most common upstream partners were CD74 (45%), SLC3A2 (31%), and SDC (9%). Most patients were female (64%) and never smokers (58%). Histology was adenocarcinoma in 95% (IMA, 91%), squamous 4%, large cell neuroendocrine 1%. At diagnosis, most patients had non-metastatic disease (stage: I 33%, II 27%, III 18%, IV 22%). The lifetime frequency of brain metastases was 15%. 12 patients received the HER2 inhibitor afatinib for stage IV disease. PD was the best response in 55% (n = 6/11) of evaluable patients with 18% PR (n = 2/11) and SD 18% (n = 2/11); median PFS was 3.5 months (range 0.6-16.5 months). 19 patients received platinum-based chemotherapy; most patients had SD as their best response (47%, n = 8); PD 41% (n = 7), PR 12% (n = 2). PD-L1 was negative in the majority of tumors (79%, n = 26/33) and none had high PD-L1 expression (range 0-20%). No responses to single-agent anti-PD-1/L1 therapy were observed (PD n = 5/6, SD n = 1/6: nivolumab/atezolizumab). No responses to chemoimmunotherapy (carboplatin, pemetrexed, pembrolizumab) were observed (SD n = 4/5, PD n = 1/5). Conclusions: RNA-based testing is an important component of NRG1 fusion detection. Novel targeted therapeutic approaches are needed as overall outcomes with afatinib are poor. NRG1 fusion-positive NSCLCs do not highly express PD-L1 and outcomes with immunotherapy ± chemotherapy are poor.

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Favorable Outcome in Patients with Acute Myeloblastic Leukemia (AML) with NPM1 Mutation Who Present an Inadequate Clearance or Relapse of Minimal/Measurable Residual Disease (MRD): Results of a Preemptive Intervention Policy (CETLAM-2012 Protocol)

Blood ◽

10.1182/blood-2018-99-110895 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1385-1385

Author(s):

Alex Bataller Torralba ◽

Marina Diaz-Beyá ◽

Ana Garrido ◽

Susana Vives ◽

Mar Tormo ◽

...

Keyword(s):

Salvage Therapy ◽

Significant Proportion ◽

Tumor Burden ◽

High Dose ◽

Molecular Response ◽

Consolidation Therapy ◽

Npm1 Mutation ◽

Free Survival ◽

Failure Risk ◽

Intervention Policy

Abstract Introduction Patients diagnosed with AML with NPM1mutation (NPM1mut AML) included in the European LeukemiaNet favorable genetic risk category (ELNfav, i.e., without FLT3-ITD or with a low allelic burden FLT3-ITD comutation [FLT3-ITD/FLT3wt <0.5; FLT3-ITDLOW]) do not benefit from an allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). However, a significant proportion of these patients fail to frontline chemotherapy and require salvage therapy. Persistence or detection of MRD after post-CR treatment is associated with a high relapse risk and worse prognosis. With this background, the cooperative group CETLAM proposed an early therapeutic intervention in CETLAM-2012 protocol for patients with ELNfavNPM1mut AML patients not achieving a sustained MRD clearance after consolidation therapy, defined as molecular failure (MF). Herein we analyzed the outcome and predictive risk factors of MF. Methods All patients diagnosed with ELNfav NPM1mut AML treated according to CETLAM-12 protocol who achieved CR after 1 or 2 courses of induction chemotherapy were included in the study. Intended post-CR therapy consisted of 3 courses of high-dose cytarabine chemotherapy (HDAC). MRD was assessed in bone marrow samples after each chemotherapy course and thereafter, at regular 3-month interval during 3 years, in reference labs from CETLAM group following standard NPM1-mutation specific RQ-PCR. MF was defined as failure to achieve a molecular response (molCR) after consolidation therapy (i.e., NPM1mut/ABL·100 ratio > 0.05) or MRD reappearance after molCR. All MFs were confirmed in a second sample collected at least 4 weeks apart from previous sample. For patients who present a MF, alloSCT was recommended, without a predefined indication of debulking previous salvage chemotherapy. Results Out of 145 patients with ELNfav NPM1mut AML (75 M/70 F; median age, 56, 18-74), 132 (91%) achieved CR after 1 (n=124) or 2 courses (n=8). After a median follow-up of 25 months, 2-year overall survival (OS), event-free survival (EFS), leukemia-free survival (LFS) of the entire cohort were 79.9% (±3.6), 71.8% (±4) and 79.4% (±3.8), respectively. Among patients with available complete MRD information (n=89), 33 patients developed an hematological and/or molecular failure (Mol/Hem failure), resulting into a Mol/Hem failure-free survival at 2 years of 62% (±5.6%); median time from CR to Mol/Hem failures was 8.2 months (2-43). Fourteen patients presented with an overt hematological relapse (hREL), preceded by a detectable MF in 8. Overall, 14 received salvage therapy in morphological CR, MRD(+) status (MF), and 14 For hREL. Among MF, 5 patients received HDAC-type salvage treatment (followed by alloSCT in 3) and 9 proceeded directly to alloSCT. In 5 additional MF patients with MRD persistence after consolidation, subsequent MRD monitoring showed decreasing MRD levels until complete clearance (n=4) or intermitent detection (n=1) and have not received further therapy. After salvage therapy, 12/14 (86%) patients with MF achieved molCR, and 10/14 (71%) treated for hREL achieved CR2 (MRD negative in 7, 50%), followed by alloSCT in 9. OS after Mol/Hem failure was 64.8% (± 8.4) at 2 years, 88.8 (±7.5%) in patients treated for MRD(+)-status (MF) and 32.1% (±13.6%) in patients treated with overt hREL (p<0.001; figure 1). Potential predictive factors of Mol/Hem failure were investigated. Interestingly, a ratio of NPM1mut/ABL*100 ≥1 after induction allowed distinction of two patient subpopulation with strikingly different Mol/Hem failure risk: Mol/Hem failure-free survival at 2 years of 84±6% vs. 33±10% in patients with a lower (<1) and higher (³1) tumor burden (p<0.001; figure 2). Remarkably, concurrence of FLT3-ITDLOWdid not correlate with outcome or Mol/Hem failure risk. Conclusion Despite a significant proportion of Mol/Hem failures, NPM1mut AML patients allocated in the ELN favorable risk group presented a favorable overall outcome. NPM1mut-based MRD surveillance is able to anticipate most hematological relapses, and a MRD-driven early intervention policy, at time of MF, allowed a successful rescue of a significant proportion of patients. Moreover, an early measure of residual tumor burden, after induction therapy, might identify those patients with a high risk of molecular or hematological subsequent failure, allowing the potential implementation of preemptive intensification strategies. Disclosures No relevant conflicts of interest to declare.

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Durvalumab in frail and elder patients with stage four NSCLC: Study protocol of the randomized phase II DURATION trial

10.21203/rs.2.16770/v3 ◽

2020 ◽

Author(s):

Jonas Kuon ◽

Adriane Hommertgen ◽

Johannes Krisam ◽

Felix Lasitschka ◽

Albrecht Stenzinger ◽

...

Keyword(s):

Adverse Events ◽

Elderly Patients ◽

Phase Ii ◽

Performance Status ◽

Single Agent ◽

Eastern Cooperative Oncology Group ◽

Stage Iv ◽

Open Label ◽

Randomized Phase Ii ◽

The Impact

Abstract Background: Elderly patients represent a major fraction of non-small cell lung cancer (NSCLC) patients in routine clinical practice, but they are still underrepresented in clinical trials. In particular, data regarding efficacy and safety in frail or elderly patients with respect to immunotherapy are lacking. Importantly, immunosenescence in elderly patients might interfere with activities of immune-modulating drugs such as PD-1/PD-L1 inhibitors. Thus, there is an urgent need to assess safety and efficacy of such inhibitors in this group. Methods/design: In this prospective, open label, treatment stratified, and randomized phase II study, 200 patients with stage IV NSCLC amenable at least to single-agent chemotherapy (CT). Eligible patients must be 70 years or older and/or “frail” (Charlson Comorbidity Index >1) or have a restricted performance status (Eastern Cooperative Oncology Group, ECOG >1). Patients are stratified according to modified Cancer and Age Research Group (CARG) score:”fit” patients are allocated to combination CT (carboplatin/ nab -paclitaxel), “less fit” patients receive single-agent CT (gemcitabine or vinorelbine). After allocation to strata, patients are randomized 1:1 to receive either 4 cycles of CT or 2 cycles of CT followed by 2 cycles of durvalumab and subsequent maintenance treatment with durvalumab every 4 weeks. The primary endpoint is the rate of treatment related grade III/IV adverse events (Common Terminology Criteria for Adverse Events, CTCAE V4.03). As secondary endpoints, progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, response rate (RR), overall survival (OS), descriptive subgroup analyses according to PD-L1 expression, and quality of life are addressed. Geriatric screening assessments and functional tests will be performed to complete the phenotyping of a potential “frail” and “elderly” patient cohort. The trial is accompanied by a biomaterial repository to explore potential biomarkers. Discussion: The DURATION trial will prospectively investigate the safety and tolerability of anti-PD-L1 treatment with durvalumab after chemotherapy in elderly and frail patients and thereby provide new insights into the effect of PD-L1 blockade and the impact of immunosenescence in this cohort of patients.

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