response criteria
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2022 ◽  
Vol 11 ◽  
Author(s):  
Rafael Alonso ◽  
Juan José Lahuerta

The development of new resources for a more accurate diagnosis and response assessment in multiple myeloma has been a long process for decades, mainly since the middle of the 20th century. During this time, the succession of technical advances has run parallel to the better knowledge of disease biology and the availability of novel therapeutic strategies. The cornerstone of standardized criteria to uniformly evaluate the disease response in myeloma dates back to the 1990s when the key role of complete remission was established. Since then, different updates have been implemented according to available scientific evidences not always without certain controversies. The progressive improvements in survival results of myeloma patients and the growing quality of responses due to the novel therapies have led to the need of developing new tools for better monitoring of tumor burden. In this way, the concept of minimal residual disease and its key value based on the prognostic significance and the clinical relevance has been consolidated during the last years, overcoming the value of conventional response criteria or classical adverse prognosis markers. Nevertheless, its precise role in the clinical management of myeloma patients to detect early treatment failure and trigger early rescue strategies is still pending to be defined. In this review, we revisit the major milestones in the understanding of tumor reduction in multiple myeloma until the most recent imaging techniques or liquid biopsy approaches, including a critical view of conventional response criteria, whose backbone has remained unchanged during the last 20 years.


2022 ◽  
Author(s):  
Guillermo Ponce de León-Ballesteros ◽  
Hugo A. Sánchez-Aguilar ◽  
Maureen Mosti ◽  
Miguel F. Herrera

2021 ◽  
pp. 110054
Author(s):  
Riccardo Guglielmi ◽  
Gustav Andreisek ◽  
Benjamin S. Halpern

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Yasmin Adel ◽  
Mohamed Sabry ◽  
Amr Mohamed El-Sabbagh ◽  
Yousra Sadeq

Abstract Background JAK (Janus kinase) inhibitors work by inhibiting the activity of one or more of the enzyme Janus kinase with a therapeutic application for treatment of cancer and inflammatory disorders such as rheumatoid arthritis (RA). We aimed to study impact of JAK2 mutation in serum of rheumatoid arthritis patients on response to first line with conventional synthetic disease-modifying anti-rheumatic drug (csDMARDS) at 3rd month by evaluating DAS28 and ACR response criteria. The study included 85 newly diagnosed rheumatoid arthritis patients and 50 matched controls. Basal JAK2 mutation assessed by PCR in blood samples, TNF-α and IL 6 were measured by ELISA in serum of patient and control groups. All patients started therapy with csDMARDs. Response assessment at 3rd month was evaluated by DAS28 and ACR response criteria. JAK2 mutation was correlated with different clinical and laboratory parameters of patients. Results Seventeen females (83.5%) and 14 males (16.5%) with age mean ± SD (years); (48.7 ± 7.2). Pretreatment JAK2 mutation, TNF-α and IL 6 were significantly high in patients. JAK2 mutation was detected in 45 (52.9%) patients while 40 (47.1%) patients were JAK2 non-mutant. Mutant JAK2 was significantly linked to severity of disease evaluated by DAS28; 14 (70%) of patients with DAS28 (≤ 2.6) were non-mutant JAK2 vs sex (30%) patients mutant JAK2 while 19 (73.1%) of patients with DAS28 (> 5.1) were mutant JAK2 vs 7 (26.9%) patients non-mutant JAK2 (P 0.02). JAK2 mutation found to be significantly correlated with ACR 20, 50, and 70 response criteria; 68.2% of patients with non-mutant JAK2 showed ACR 70 vs 31.8% in mutant group, 52% of patients with non-mutant JAK2 showed ACR 50 vs 48% in mutant group while 31.6% of patients with non-mutant JAK2 showed ACR 20 vs 68.4% in mutant group (P 0.02). JAK2 mutation were more presented in young age patients (mean ± SD; 47.1 ± 7.2 vs 50.4 ± 6.9 in mutant vs non-mutant JAK2 patients, respectively with P 0.03). JAK2 mutation was associated with high pretreatment TNFα and IL6 level in serum. Mean ± SD of TNFα; 49.4 ± 41.9 in mutant vs 26 ± 24.4 pg/ml in non-mutant group, with P (0.003) while mean ± SD of IL6; 83.5 ± 56.8 in mutant vs 47 ± 46.9 pg/ml in non-mutant group, with P (0.002). Conclusions Adult RA with pretreatment JAK2 mutation significantly showed high disease activity and high pretreatment TNFα and IL6 levels. Patients with JAK2 mutation found to be linked to poor response to 1st line csDMARDs including MTX so they could get more benefit with early introduction of JAK inhibitors as first line monotherapy or when combined with csDMARDS especially those with moderate to severe active RA. Trial registration Institutional Research Board (IRB)-Faculty of Medicine: IRB Proposal Code: R.20.11.1075-2020/11/16. Clinicaltrials.gov registration date: 8/12/2020, code: NCT04667988.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1379-1379
Author(s):  
Jane N. Winter ◽  
Akash Nahar ◽  
Eunhee Kim ◽  
Patricia Marinello

Abstract Background: Immunotherapeutic strategies targeting the PD-1/PD-L1 pathway have become part of standard of care for patients with classical Hodgkin lymphoma (cHL). Recent studies have investigated combinations of anti-PD-1 antibodies with conventional chemotherapy and demonstrated significant clinical benefits in the first-line setting. A phase 2 trial demonstrated that induction with pembrolizumab monotherapy followed by chemotherapy was highly effective and safe in patients with newly diagnosed, early unfavorable, or advanced-stage cHL (Allen PB et al. Blood. 2020;137[10]:1318-1326). The KEYNOTE-C11 open-label phase 2 study will build on this concept by evaluating the safety and efficacy of sequential pembrolizumab monotherapy and chemotherapy followed by pembrolizumab consolidation in adult patients with newly diagnosed, early unfavorable, or advanced-stage cHL. Study Design and Methods: Patients must have newly diagnosed, histologically confirmed, untreated (no prior chemotherapy, immunotherapy, or other systemic therapy for cHL), early unfavorable cHL (Ann Arbor stage I/II plus ≥1 National Comprehensive Cancer Network unfavorable risk factor) or advanced-stage cHL (Ann Arbor stage III/IV) and measurable disease per Lugano 2014 classification. Approximately 140 patients will be enrolled. All patients will receive pembrolizumab 200 mg IV every 3 weeks (Q3W) for 3 cycles followed by PET to determine response to pembrolizumab monotherapy. After pembrolizumab induction, all patients will receive 2 cycles of AVD (day 1 and day 15 Q4W) and undergo another assessment by PET (PET 3) to determine the next treatment course. Patients with negative findings on PET 3 (≤3 on the Deauville 5-point scale) will receive 2-4 additional cycles of AVD, depending on stage and bulk of disease; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will proceed to 4 cycles of AVD chemotherapy. Patients who are PET 3+ (≥4 on the FDG-PEG 5-point scale) and aged <60 years will transition to 2-4 cycles of escBEACOPP; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will receive 4 cycles. Patients aged ≥60 years who are PET 3+ will not transition to escBEACOPP and will continue to receive AVD. Finally, all patients will receive 4 cycles of pembrolizumab 400 mg Q6W after the completion of chemotherapy. They will remain on study treatment until disease progression, unacceptable toxicity, illness preventing continuation, investigator's decision, or maximum duration of treatment, which will include 4 cycles of pembrolizumab consolidation. Adverse events will be graded per CTCAE version v5.0. The primary end point is complete response assessed by blinded independent central review (BICR) per Lugano 2014 response criteria. Secondary end points include complete response by investigator per Lugano 2014 response criteria, BICR-assessed PET negativity (score of 1, 2, or 3 per FDG-PET 5-point scale), BICR-assessed duration of complete response per Lugano 2014 response criteria, and safety and tolerability. Exploratory end points include modified progression-free survival and overall survival. The efficacy and safety analysis population will consist of all patients who received ≥1 dose of pembrolizumab. The complete response rate with 95% CI will be reported per the Clopper-Pearson exact binomial method. Duration of complete response, progression-free survival, and overall survival will be evaluated using Kaplan-Meier method. Counts and percentages of patients with adverse events will be provided. Disclosures Winter: Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy; Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria. Nahar: Merck: Current Employment. Kim: Merck: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3701-3701
Author(s):  
Jan Philipp Bewersdorf ◽  
Wei Wei ◽  
Anna Jaiani ◽  
Prital Patel ◽  
Rajni Mehta ◽  
...  

Abstract Introduction: Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients (pts) with myelodysplastic syndromes (MDS). Response in MDS is based on the modified International Working Group (IWG) 2006 criteria. Prior studies focusing on unselected MDS pts showed that achieving a complete remission (CR) was associated with favorable overall survival (OS). However, the association of other outcomes with OS was less clear and only 20% of HMA-treated MDS pts achieve a CR. For example, pts who achieved <5% bone marrow (BM) blasts are currently classified as marrow CR (mCR), which has not been associated with OS improvement. Therefore, interpreting the significance of mCR reported in various clinical trials is challenging. Clinically meaningful reduction in bleeding or infectious complications can occur at improvements in absolute neutrophil count (ANC) and platelet counts that do not meet the current thresholds used for CR (ANC ≥1.0 × 10 9/L, platelets ≥100 × 10 9/L, and Hb >11 g/dL). To avoid missing clinically meaningful benefits when studying new drugs in clinical trials, a clearly defined response criterion that is less stringent than CR but still captures clinically meaningful hematologic improvement (HI) is needed. Here we sought to evaluate the impact of current IWG 2006 response criteria as well as CRh on OS of pts with HR-MDS treated with frontline HMA monotherapy. Methods: We included all adult (≥18 years) MDS pts treated with frontline HMA (azacitidine [AZA], decitabine [DEC], or ASTX727) monotherapy between 1/1/2012 and 12/31/2020 at Yale University. We decided to use HMA monotherapy as it is the standard care for HR-MDS and to minimize the impact of therapy choice confounding the association of achieved response with OS. Pts were excluded if they received prior treatments for MDS aside from erythropoiesis-stimulating agents and if no baseline with at least one follow-up BM study were available for response assessment. We collected patient and disease characteristics (transfusion burden, IPSS/IPSS-R score, cytogenetics, molecular studies) at baseline. Best responses were assessed based on IWG 2006 criteria for MDS. We defined CRh as <5% BM blasts, platelets ≥50 × 10 9/L, ANC ≥0.5 × 10 9/L and no peripheral blood blasts. We followed pts until death or last follow-up and recorded dates of allogeneic hematopoietic cell transplant (HCT) if applicable. Date of data cut-off for survival status was 5/31/2021. We performed Kaplan-Meier analysis to estimate the duration of overall survival and we used log rank test to test the difference in OS between subgroups of pts. Multiple comparisons were adjusted using the Bonferroni method. Results: A total of 100 pts was included in this analysis (Table 1). Median age was 68 years (yrs; range, 23 - 86), 60% were males, and 79% and 18% of pts received AZA and DEC, respectively. Median number of HMA cycles was 6 (interquartile range [IQR]: 4-10), and 33 pts (33%) underwent HCT. During follow-up, 46 pts (48%) progressed to AML. At a median follow-up of 1.5 yrs (IQR: 0.9 - 2.3 yrs), median OS for the entire pt cohort was 1.9 yrs (Figure 1). OS by response category is shown in Table 2. Median OS was not reached for patients who achieved a CR (95% CI: not reached [NR] - NR) as compared to 1.9 yrs (95% CI: 1.5 yrs - NR) and 2.0 yrs (95% CI: 1.2 yrs - NR) among pts with mCR + HI and mCR without HI, respectively. Median OS among patients with stable disease (SD) was similar (2.0 yrs [95% CI: 1.5 yrs - NR]). Finally, we explored the prognostic value of CRh and found a median OS of 1.9 yrs (95% CI: 1.5 yrs - NR), which appeared comparable to mCR +/- HI or SD. Similar results were found with censoring at time of HCT (Figure 2). Discussion: In this retrospective analysis of MDS pts treated with HMA monotherapy in the frontline setting, achieving CR as best response was associated with improved OS compared with mCR +/- HI and SD. However, as the numbers were small these results should be interpreted with caution, and other clinically relevant outcomes such as freedom of transfusion, infectious or bleeding complications, and patient-reported outcomes were not captured in the current analysis. Our results also apply only to MDS pts treated with HMA monotherapy in the frontline setting. The prognostic implications of CRh need to be evaluated in larger patient cohorts. To overcome these limitations, we are currently in the process of expanding the study to a much larger multi-center, international analysis. Figure 1 Figure 1. Disclosures Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Pfizer: Honoraria; CTI BioPharma: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Brunner: GSK: Research Funding; Aprea: Research Funding; Keros Therapeutics: Consultancy; Agios: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Janssen: Research Funding. Zeidan: AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; Amgen: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Acceleron: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Jasper: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Astex: Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Astellas: Consultancy.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2177-2177
Author(s):  
Ma Evette Barranta ◽  
Fariba Chinian ◽  
Katherine Roskom ◽  
Tarik Lott ◽  
Julie Erb-Alvarez ◽  
...  

Abstract Fanconi anemia (FA) is an inherited disorder associated with loss of function mutations in gene members of the FA-BRCA pathway involved in interstrand cross-link DNA damage repair during cell division. Progressive bone marrow failure (BMF) is a primary cause of morbidity and mortality in patients with FA. Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation is the only curative treatment for FA-associated BMF. However, donor availability, graft failure, and FA-specific transplant toxicities remain significant hurdles. Attempts at genetic correction of FA are underway but collection of sufficient numbers of autologous HSPCs is challenging in subjects with advanced BMF. Androgens have been successfully used but side effects often prevent prolonged therapy. The orally bioavailable small molecule mimetic of thrombopoietin, eltrombopag (EPAG), was recently shown to stimulate multipotent long-term repopulating HSPCs in patients with acquired BMF, resulting in persistent trilineage hematopoiesis. EPAG promotes DNA repair (Guenther, Exp Hematol 2019) and maintains HSPCs under inflammatory conditions (Alvarado, Blood 2019), indicating potential relevance in FA. In this study, we investigated whether EPAG may offer a novel therapeutic modality for FA-associated BMF. We have enrolled 10 patients (FANCA, n=9 and FANCC, n=1) to date in a prospective phase I/II study of EPAG in Fanconi anemia (NCT03204188). All subjects received EPAG at an oral daily dose adjusted for age and ethnicity. The primary efficacy endpoint was the proportion of subjects with at least 2-fold increase in marrow cellularity or CD34+ HSPC frequency (marrow response), or clinically significant improvement in peripheral blood (PB) counts at 6 months (blood response). The primary safety endpoint was the global toxicity profile assessed at 6 months using CTCAE criteria. Responders were invited to continue on the extension phase of the study for an additional 3 years. Four of 10 patients have reached the 6-month assessment endpoint, and a pre-specified 3-month interim analysis is available on two additional subjects. A marrow response was observed in all 4 subjects at 6 months. Mean marrow cellularity increased by a factor of 4 (Fig. A/B), and CD34+ HSPC frequency improved 2.5-fold at 6 months relative to pre-treatment values (Fig. C/D). Marrow response criteria were also met in the other two subjects at the 3-month interim assessment. Primary PB response was observed in 2 of 4 patients in one (hemoglobin) or two lineages (hemoglobin and platelets) at 6 months of treatment. Responders continue to receive EPAG at 10 or 25 months with sustained improvements in blood counts and transfusion independence. The subject treated for 25 months recently met response criteria in a third lineage (neutrophils) (Fig. E). Both patients who had a marrow but no PB response are clinically well; one subject (FANCA) underwent an unrelated allogeneic HSPC transplantation one year ago, and the other subject (FANCC) recently entered the extension phase of this study. Unilineage PB response criteria were also met in one of two subjects at the 3-month interim assessment. No drug-related serious adverse events have occurred during EPAG treatment. All patients tolerated the maximum dose of EPAG and no interruption or dose reduction was required for adverse events attributable to EPAG. Patients without transfusional iron overload at study entry developed progressive depletion of iron stores attributable to the known potent iron chelating and mobilizing properties of EPAG. At a median of 3 months after initiating EPAG (range, 1 to 6 months), affected patients initiated daily oral iron supplementation with gradual amelioration of iron store levels. To date, there has been no occurrence of marrow fibrosis, solid malignancies or clonal evolution, defined as abnormalities on standard metaphase analysis of bone marrow or overt clinical transformation to MDS/AML. In sum, treatment with EPAG was associated with increased marrow HSPCs in all subjects and PB responses in a subset of patients with Fanconi anemia. The overall safety profile was favorable. Further follow-up and expansion of the ongoing patient cohort will confirm EPAG's potential as a safe and efficient long-term therapeutic modality for FA-associated BMF. Alternatively, EPAG could also be used safely to boost marrow CD34+ cell numbers prior to autologous gene therapy applications. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 10 (21) ◽  
pp. 5160
Author(s):  
Egesta Lopci

Immunotherapy with checkpoint inhibitors has prompted a major change not only in cancer treatment but also in medical imaging. In parallel with the implementation of new drugs modulating the immune system, new response criteria have been developed, aiming to overcome clinical drawbacks related to the new, unusual, patterns of response characterizing both solid tumors and lymphoma during the course of immunotherapy. The acknowledgement of pseudo-progression, hyper-progression, immune-dissociated response and so forth, has become mandatory for all imagers dealing with this clinical scenario. A long list of acronyms, i.e., irRC, iRECIST, irRECIST, imRECIST, PECRIT, PERCIMT, imPERCIST, iPERCIST, depicts the enormous effort made by radiology and nuclear medicine physicians in the last decade to optimize imaging parameters for better prediction of clinical benefit in immunotherapy regimens. Quite frequently, a combination of clinical-laboratory data with imaging findings has been tested, proving the ability to stratify patients into various risk groups. The next steps necessarily require a large scale validation of the most robust criteria, as well as the clinical implementation of immune-targeting tracers for immuno-PET or the exploitation of radiomics and artificial intelligence as complementary tools during the course of immunotherapy administration. For the present review article, a summary of PET/CT role for immunotherapy monitoring will be provided. By scrolling into various cancer types and applied response criteria, the reader will obtain necessary information for better understanding the potentials and limitations of the modality in the clinical setting.


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