scholarly journals Where does transplant fit in the age of targeted therapies?

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 287-293 ◽  
Author(s):  
Victor A. Chow ◽  
Ajay K. Gopal
Keyword(s):  
Follicular Lymphoma ◽  
Hematopoietic Cell Transplantation ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Low Toxicity ◽  
First Recurrence ◽  
Autologous Hct

Abstract The role of hematopoietic cell transplantation (HCT) for indolent lymphoma has evolved over the last 5 years with the availability of novel low-toxicity therapies and a better understanding of the prognosis of these entities. However, despite numerous treatment options for patients with follicular lymphoma, none are thought to be curative, and many require ongoing therapy with chronic toxicity. Historical trials indicate that autologous HCT as initial consolidation leads to improved progression-free survival, but not overall survival (OS) and, thus, is not typically recommended. However, autologous HCT for chemosensitive relapse can be carried out with ∼1% early mortality risk, affording disease control lasting a median of 3 to 5 years and the potential to improve OS. These results may compare favorably in efficacy, toxicity, and cost vs multiple sequential novel therapies with shorter durations of benefit. Recent data indicate that autologous HCT in follicular lymphoma patients with early initial progression will result in more than one third being alive and without relapse at 5 years, leading to improved OS when used within a year of the first recurrence. Unlike other available therapies, allogeneic HCT has the potential to cure up to one half of those transplanted with indolent B-cell non-Hodgkin lymphoma, although the risks need to be recognized and appropriate patient and donor selection is critical to ensure the best outcomes. HCT continues to remain a viable option in the current era of multiple targeted agents.

Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2650-2657 ◽  
Author(s):  
Hervé Ghesquières ◽  
Guillaume Cartron ◽  
John Francis Seymour ◽  
Marie-Hélène Delfau-Larue ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Follicular Lymphoma ◽  
Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Free Survival ◽  
Rituximab Maintenance

Abstract In patients with follicular lymphoma treated with single-agent rituximab, single nucleotide polymorphisms in the FCGR3A gene are known to influence response and progression-free survival. The prognostic role of FCGR3A and FCGR2A polymorphisms in patients with follicular lymphoma treated with rituximab and chemotherapy combination remains controversial and has not been evaluated in the context of rituximab maintenance. FCGR3A and FCGR2A single nucleotide polymorphisms were evaluated in, respectively, 460 and 455 patients treated in the PRIMA study to investigate whether these were associated with response rate and patient outcome after rituximab chemotherapy induction and 2-year rituximab maintenance. In this representative patient cohort, complete and unconfirmed complete responses after rituximab chemotherapy were observed in 65%, 67%, 66% (P = .86) and 60%, 72%, 66% (P = .21) of FCGR3A VV, VF, FF and FCGR2A HH, HR, RR carriers, respectively. After 2 years of rituximab maintenance (or observation), response rates did not differ among the different genotypes. Progression-free survival measured from either treatment initiation or randomization to observation or maintenance was not influenced by these polymorphisms. These data indicate that FCGR3A and FCGR2A polymorphisms do not influence response rate and outcome when rituximab is combined with chemotherapy or used as maintenance treatment. The PRIMA study is registered at www.clinicaltrials.gov as NCT00140582.

The role of obinutuzumab in the management of follicular lymphoma

2019 ◽  
Vol 15 (31) ◽  
pp. 3565-3578 ◽  
Author(s):  
Jenny O’Nions ◽  
William Townsend
Keyword(s):  
Clinical Trials ◽  
Follicular Lymphoma ◽  
Progression Free Survival ◽  
Free Survival ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Almost All ◽  
Cd20 Antibodies

The outcomes for follicular lymphoma (FL) have improved significantly in recent years. This has been driven by an improved understanding of the pathobiology of FL and the development of therapeutic anti-CD20 antibodies. Combining rituximab with chemotherapy, coupled with its use as maintenance therapy, has contributed to significant improvements in disease control and progression-free survival. However, FL remains incurable and almost all patients invariably relapse. Therefore, there remains a need to develop novel therapeutic options and optimize existing regimens. Obinutuzumab (a first-in-class, glycoengineered, humanized type 2 anti-CD20 antibody) has been evaluated in a number of clinical trials. In this review, we will summarize the evaluable results of clinical trials investigating the efficacy of obinutuzumab in the treatment of FL.

Results of Alemtuzumab-Based Reduced-Intensity Allogeneic Transplantation for Advanced Chronic Lymphocytic Leukemia: A BSBMT Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2899-2899
Author(s):  
Julio Delgado ◽  
Kirsty Thomson ◽  
Nigel Russell ◽  
Joanne Ewing ◽  
Wendy Stewart ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Fungal Infections ◽  
Progression Free Survival ◽  
Allogeneic Transplantation ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Autologous Hct ◽  
Reduced Intensity ◽  
Related Mortality

Abstract We report 41 consecutive patients with advanced chronic lymphocytic leukemia (CLL) who underwent allogeneic hematopoietic cell transplantation (HCT) following fludarabine, melphalan and alemtuzumab reduced intensity conditioning. Donors were 24 HLA-matched siblings and 17 unrelated volunteers (4 of them mismatched). Median age at transplant was 54 (range 37–67) years, interval from diagnosis to HCT was 54 (10–164) months, and number of previous chemotherapy regimens was 3 (1–6). Eleven patients were refractory to fludarabine at the time of transplant and 3 others (8%) had it stopped due to immune cytopenias. Eleven patients had failed autologous HCT. At the time of transplant, 7 patients (17%) had chemo-refractory and 34 (83%) chemo-sensitive disease, but only 5 (12%) were in complete remission. All but 3 patients had initial hematological recovery, but 5 more patients had delayed graft failure that responded to subsequent stem-cell infusions. Median intervals to neutrophil (> 0.5 × 109/l) and platelet (> 20 × 109/l) recovery were 14 (range 9–30) and 11 (range 8–45) days, respectively. Eleven patients (27%) relapsed and received escalated donor lymphocyte infusions, but only 3 of them had a sustained response. Acute and chronic graft-versus-host disease (GVHD) was observed in 17 (41%) and 13 (33%) patients, respectively. With a median follow-up of 15 (range 0.2–62) months, 17 patients have died, 5 of progressive disease and 12 of transplant-related complications. The 2-year overall survival, progression-free survival and transplant-related mortality are 51% (CI 33%–69%), 45% (27%–62%) and 26% (14%–46%), respectively (Figure 1). In multivariate analysis, fludarabine refractoriness prior to transplant was the only factor to predict a worse progression-free survival in this setting. In conclusion, the alemtuzumab-based regimen was feasible and effective in patients with CLL with a relatively low rate of GVHD. However, transplant-related mortality remains relatively high as a result of a variety of viral and fungal infections. Ongoing studies are aiming to address the efficacy of reduced doses of alemtuzumab in this group of very immunosupressed patients. Figure Figure

Unrelated Donor KIR B/X Genotype Reduces Relapse and Improves Progression-Free Survival after HLA-Matched Allogeneic Transplantation for Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 670-670
Author(s):  
Veronika Bachanova ◽  
Daniel J. Weisdorf ◽  
Tao Wang ◽  
Steven G.E. Marsh ◽  
Elizabeth Trachtenberg ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Nk Cells ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Free Survival ◽  
Kir Genes ◽  
Non Hodgkin Lymphoma

Abstract While allogeneic donor hematopoietic cell transplantation (HCT) can cure non-Hodgkin lymphoma (NHL) by inducing a graft-versus-lymphoma effect, 10-35% of patients experience progression or relapse. We investigated whether the genotype of allogeneic donor natural killer (NK) cell killer immunoglobulin-like receptors (KIR) impacts the survival of lymphoma patients. The importance of KIR genetics in unrelated donor (URD) HCT has been demonstrated in AML where donors with favorable KIR gene content reduced the risk of relapse by 30%. Because the consequence of donor KIR genotype in NHL is unknown, we evaluated its effect on transplant outcome in 614 adults with NHL (28% follicular lymphoma, 16% diffuse large B cell lymphoma, 17% mantle cell lymphoma, 37% other) who underwent T cell replete URD HCT between 1990-2009 with outcomes reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor samples from the NMDP/CIBMTR Repository were genotyped (15 KIR genes) by MALDI-TOF mass spectroscopy. KIR haplotypes (A/A or B/x) were determined by presence/absence of individual KIR genes. Multivariate regression models were used to test the associations between donor KIR genotype and clinical outcome. The median patient age was 50 years (range 19-72), 93% were Caucasians and 62% had chemosensitive lymphoma. Most (60%) were >1.5 years from diagnosis; 41% received myeloablative preparative regimens and 61% received peripheral blood derived grafts. Most transplants were 10/10 matched for HLA alleles (n=396), the remainder 9/10 matched (n=158) or ≤8/10 matched (n=60). The frequencies of KIR genotypes in donors reflected the Caucasian population: 70% (n=428) were KIR B/x and 30% (n=180) were KIR A/A. Patients receiving 10/10 HLA-matched grafts (65%) experienced significantly lower relapse at 5 years when donors were KIR B/x genotype (n=281; 26% [95%CI 21-32%]) compared to KIR A/A genotype (n=115; 37% [95% CI 27-46%] ;p=0.05; Figure left) leading to improved progression-free survival (PFS) (35% [95% 26-44] vs. 22% [95%CI 11-35%]; p=0.02; Figure right). After adjusting for significant clinical variables, KIRB/x donors conferred significant protection against relapse (RR 0.63 [95%CI 0.43-0.92]; p=0.02) and improved PFS (RR 0.71 [95% CI 0.55-0.91]; p=0.008) compared to KIR A/A donors. The relapse protection and improved survival associated with KIR B/x donors was highly significant in the 10/10 HLA matched cohort (n=396) but not in the HLA-mismatched transplants (n=218; PFS RR 1.21 [95%CI 0.86-1.7]; Relapse RR 1.49 [0.87-2.55], p=NS for both). Importantly, the use of KIR B/x donors was associated with improved clinical outcomes for patients after both myeloablative and reduced intensity conditioning. Donor KIR genotype had no effect on rates of acute graft-versus-host disease (HR 1.05; p=0.86), and treatment related mortality at 1 year was similar for both groups (28% [B/x] and 30% [A/A]). In multivariate analysis of the entire cohort, other factors adversely impacting PFS included chemoresistant lymphoma (HR 1.52; p=0.03), disease other than follicular lymphoma (HR 1.34; p=0.0001) and <1.5 years interval from diagnosis to HCT (HR 1.35; p=0.003). Our results demonstrate that donors with KIR B/x genotypes, whose NK cells express more activating KIR, are associated with decreased relapse and improved survival after 10/10 HLA-matched URD HCT for NHL. The results suggest that NK cells may contribute to graft-versus-lymphoma effects and support the consideration of KIR genotyping with HLA typing into URD search criteria for patients with NHL. Figure 1 Figure 1. Disclosures Miller: Coronado: Speakers Bureau; BioSciences: Membership on an entity's Board of Directors or advisory committees; SAB: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

New Treatment Options Have Changed the Survival of Patients With Follicular Lymphoma

2005 ◽  
Vol 23 (33) ◽  
pp. 8447-8452 ◽  
Author(s):  
Richard I. Fisher ◽  
Michael LeBlanc ◽  
Oliver W. Press ◽  
David G. Maloney ◽  
Joseph M. Unger ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Study Groups ◽  
Initial Therapy ◽  
Chop Chemotherapy ◽  
Free Survival ◽  
Impact On Survival ◽  
History Of ◽  
New Treatment

Background The natural history of follicular lymphoma is believed not to have changed over the last 30 years. Median survivals have ranged from 7 to 10 years, and the disease is considered incurable. However, multiple new treatment options have been developed in the last decade, and their impact on survival of follicular lymphoma remains unknown. Patients and Methods In the current analysis, we identified all previously untreated, advanced-stage, follicular lymphoma patients treated with the following three sequential treatment approaches: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy ± nonspecific immunostimulants (Southwest Oncology Group [SWOG] 7426 and 7713: 1974 to 1983); prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE) plus mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) ± interferon (SWOG 8809: 1988 to 1994); and CHOP followed by monoclonal antibody (MoAb) therapy (SWOG 9800 and 9911: 1998 to 2000). We assessed the patients' progression-free survival (PFS) and overall survival (OS). The MoAb trials included CHOP followed by rituximab (SWOG 9800) and CHOP followed by 131I-tositumomab (SWOG 9911). Results The PFS curves for the CHOP and ProMACE-MOPP studies are overlapping, with 4-year PFS estimates of 46% and 48%, respectively. However, the PFS rate of the CHOP + MoAb studies is significantly improved at 61% (P = .005). The OS curves show improvement with each succeeding study. The 4-year estimate of OS is 69% for the CHOP regimens, 79% for the ProMACE-MOPP study, and 91% for the CHOP + MoAb regimens (P < .001). These conclusions were retained after adjusting for differences in prognostic factors between the study groups. Conclusion The results of this study suggest that OS for patients with follicular lymphoma has improved over time and that the choice of initial therapy may matter.

Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3295-3301 ◽  
Author(s):  
Marinus H. J. van Oers ◽  
Richard Klasa ◽  
Robert E. Marcus ◽  
Max Wolf ◽  
Eva Kimby ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Remission Induction ◽  
Phase 3 ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Rituximab Maintenance ◽  
Non Hodgkin Lymphoma

Abstract We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m2 intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m2 intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.

New Treatment Options Have Changed the Natural History of Follicular Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 583-583 ◽  
Author(s):  
Richard I. Fisher ◽  
Michael LeBlanc ◽  
Oliver W. Press ◽  
David G. Maloney ◽  
Thomas P. Miller
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Natural History ◽  
Follicular Lymphoma ◽  
Treatment Strategy ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Free Survival ◽  
History Of ◽  
New Treatment

Abstract The natural history of follicular lymphoma has not changed over the last 30 years (Horning, S.J., Seminars in Oncology20: 1993, 75–88). Median survivals have ranged from 7 – 10 years and the disease is generally considered incurable as there has been no plateau in the survival curve. However, multiple new treatment options, including biologic agents, have been developed in the last decade and their impact on the natural history of follicular lymphoma remains unknown. In order to determine the cumulative effects of all these new treatment options, we identified all previously untreated, advanced stage, follicular lymphoma patients treated with three sequential treatment approaches: CHOP chemotherapy +/− nonspecific immunostimulants (SWOG 7426 and 7713: 1974 – 1978), ProMACE-MOPP +/− interferon (SWOG 8809: 1988 – 1994), and CHOP followed by monoclonal antibody therapy (SWOG 9800 and 9911: 1998 – 2000) and determined their Progression-Free Survival (PFS) and Overall Survival (OS). More specificially, the monoclonal antibody trials included CHOP followed by rituximab (SWOG 9800) and CHOP followed by 131I-Tositumomab (SWOG 9911). The PFS are shown below: Progression-Free Survival by Treatment Strategy TREATMENT N DEATH/PROGRESSION 4-YR PFS CHOP + MoAb 179 75 61% ProMACE 425 290 48% CHOP 356 257 46% The results demonstrate that the PFS remained unchanged until the recent studies that utilized CHOP followed by a monoclonal antibody for initial treatment. The results of OS from these three groups are shown below. Overall Survival by Treatment Strategy TREATMENT N DEATH 4-YR OS CHOP + MoAb 179 18 91% ProMACE 425 189 79% CHOP 356 226 69% In contrast to the PFS, OS has increased with each subsequent study. These data are consistent with the hypotheses that initial therapy with chemotherapy followed by a monoclonal antibody has a significant impact on PFS (p= .005) and OS (p < .0001) and that, even in earlier studies where we could not demonstrate improved initial treatment, sequential new treatment options have also changed the OS (p < .0001) and thus the natural history of follicular lymphoma.

scholarly journals Bevacizumab plus capecitabine as later-line treatment for patients with metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yeong Hak Bang ◽  
Jeong Eun Kim ◽  
Ji Sung Lee ◽  
Sun Young Kim ◽  
Kyu-Pyo Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Median Overall Survival ◽  
Treatment Options ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Free Survival ◽  
Medical Need ◽  
Significant Disease

AbstractThere is an unmet medical need for later-line treatment options for patients with metastatic colorectal cancer (mCRC). Considering that, beyond progression, co-treatment with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate, we aimed to evaluate the efficacy of capecitabine and bevacizumab. This single-center retrospective study included 157 patients between May 2011 and February 2018, who received bevacizumab plus capecitabine as later-line chemotherapy after progressing with irinotecan, oxaliplatin, and fluoropyrimidines. The study treatment consisted of bevacizumab 7.5 mg/kg on day 1 and capecitabine 1,250 mg/m2 orally (PO) twice daily on day 1 to 14, repeated every 3 weeks. The primary endpoint was progression-free survival (PFS). The median PFS was 4.6 months (95% confidence interval [CI] 3.9–5.3). The median overall survival (OS) was 9.7 months (95% CI 8.3–11.1). The overall response rate was 14% (22/157). Patients who had not received prior targeted agents showed better survival outcomes in the multivariable analysis of OS (hazard ratio [HR] = 0.59, 95% CI 0.43–0.82, P = 0.002) and PFS (HR = 0.61, 95% CI 0.43–0.85, P = 0.004). Bevacizumab plus capecitabine could be a considerably efficacious option for patients with mCRC refractory to prior standard treatments.

scholarly journals Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 304
Author(s):  
Marta Araujo-Castro ◽  
Eider Pascual-Corrales ◽  
Javier Molina-Cerrillo ◽  
Teresa Alonso-Gordoa
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Mechanisms Of Resistance ◽  
Response Efficacy ◽  
Predictors Of Response ◽  
Primary Endpoints ◽  
Tumor Mutational Burden

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

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