Effects Of Five-Years Of Ruxolitinib Therapy On Bone Marrow Morphology In Patients With Myelofibrosis and Comparison With Best Available Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4055-4055 ◽  
Author(s):  
Hans Michael Kvasnicka ◽  
Jürgen Thiele ◽  
Carlos E. Bueso-Ramos ◽  
William Sun ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
World Health ◽  
Cancer Center ◽  
Term Therapy ◽  
Spleen Size ◽  
Collagen Deposition ◽  
Risk Of Death

Abstract Background Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis and ineffective, extramedullary hematopoiesis resulting in splenomegaly, debilitating symptoms, and shortened survival. So far, conventional pharmacotherapy had limited success in improving BM fibrosis. The JAK1/JAK2 inhibitor ruxolitinib (RUX) reduced splenomegaly and symptom burden and improved survival in patients (pts) with intermediate-2 or high-risk MF compared with placebo or best available therapy (BAT) in two phase 3 studies. We examined the effects of long-term RUX treatment on BM morphology in pts with MF from the MD Anderson Cancer Center enrolled in the phase 1/2 study (NCT00509899) and compared the results with a cohort of pts treated with BAT. Methods Trephine biopsies of pts with primary MF (PMF), post-polycythemia vera MF, or post-essential thrombocythemia were obtained at baseline and at 24 (68 pts), 48 (38 pts), 54 (24 pts), 60 (10 pts) and 66 (4 pts) months (mo) of therapy. World Health Organization (WHO)-defined BM fibrosis grade (scale 0-3) was assessed independently by two authors (JT and HMK) and reviewed by a third author (CB-R). Final grade was determined by consensus, with all reviewers blinded to pt characteristics and outcomes. Accuracy of grading was validated in randomly selected biopsies by a consortium of 8 European LeukemiaNET hematopathologists. BM fibrosis grade in 192 pts with PMF treated with BAT for 24 (97 pts), 48 (63 pts), 54 (17 pts), 60 (9 pts), or 66 (6 pts) mo was determined from prospectively collected biopsies from an independent, multicenter, observational database. The majority of BAT patients were treated with hydroxyurea [HU], various sequential therapies, or watchful waiting; few pts were treated with interferon-alpha. Biopsies were performed at protocol-defined intervals for RUX-treated pts or at the discretion of the treating physician in BAT-treated pts, mostly based on changes in a patient's clinical condition. Changes from baseline in BM fibrosis grade were categorized as improvement, stabilization, or worsening. Changes over time in the extent of collagen deposition and osteosclerosis and in BM cellularity were evaluated in RUX-treated pts only. Results At baseline, 22%, 53%, and 25% of the 68 eligible RUX-treated pts had BM fibrosis grade 1, 2, and 3, respectively. Baseline osteosclerosis grade 0, 1, 2, and 3 was present in 50%, 32%, 9%, and 9% of RUX-treated pts, respectively. Accumulation of collagen fibers at baseline was observed in 32 pts (47%), with 29% having mild (grade 1) and 18% having manifest (grade 2) or intense (grade 3) collagen deposition. BM fibrosis grade distribution at baseline did not differ significantly between RUX- and BAT-treated pts (p=0.308, Cochran–Mantel–Haenszel test). At 24, 48, and 60 mo, a greater percentage of RUX-treated pts experienced stabilization or improvement of BM fibrosis relative to their baseline status compared with BAT-treated pts. Worsening BM fibrosis was more prevalent in BAT-treated pts compared with RUX-treated pts (Table). The majority of RUX-treated pts experienced durable spleen size reductions; effect on spleen size was associated with improvement or stabilization of BM morphology. In RUX-treated pts, improvement or stabilization of BM fibrosis at 24 mo was associated with a reduced relative risk of death compared with worsening BM fibrosis at 24 mo. Conclusions Long-term therapy with RUX may provide a clinically meaningful delay of BM fibrosis progression in pts with MF. The lack of a beneficial effect of long-term BAT is consistent with previous observations in a smaller cohort of HU-treated pts (Kvasnicka et al. ASCO 2013. Abstract 7030). Improvement or stabilization of BM fibrosis with RUX may be associated with more favorable outcomes. Results from this analysis support the importance of BM fibrosis as a prognostic marker in pts with MF. Disclosures: Kvasnicka: Novartis: Consultancy; Incyte Corporation: Consultancy; Novartis: Research Funding; Incyte Corporation: Research Funding; Shire: Research Funding; AOP Orphan Pharmaceuticals: Research Funding; Novartis: Honoraria; Shire: Honoraria; Incyte Corporation: Honoraria. Thiele:AOP Orphan Pharmaceuticals: Consultancy; Incyte Corporation: Consultancy; Novartis: Consultancy; Shire: Consultancy; Sanofi: Consultancy; Novartis: Research Funding; Shire: Research Funding; AOP Orphan Pharmaceuticals: Honoraria; Incyte Corporation: Honoraria; Novartis: Honoraria; Shire: Honoraria; Sanofi: Honoraria. Sun:Incyte: Employment; Incyte: Equity Ownership. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Verstovsek:Incyte Corporation: Research Funding.

Ruxolitinib-Induced Modulation of Bone Marrow Microenvironment in Patients with Myelofibrosis Is Associated with Inflammatory Cytokine Levels

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3182-3182 ◽  
Author(s):  
Hans Michael Kvasnicka ◽  
Juergen Thiele ◽  
Carlos E. Bueso-Ramos ◽  
William Sun ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Janus Kinase ◽  
Apolipoprotein A1 ◽  
Term Therapy ◽  
Historical Cohort ◽  
Stromal Reaction ◽  
Fibrotic Process ◽  
Cytokine Levels

Abstract Background: The Janus kinase inhibitor ruxolitinib (RUX) has recently been shown to induce a meaningful reduction in bone marrow (BM) fibrosis in patients with intermediate-2 or high-risk myelofibrosis (MF) compared with best available therapy (BAT). The altered BM microenvironment in MF is generally associated with prominent pro-inflammatory changes and high levels of corresponding cytokines. We evaluated the complex BM stromal changes following up to 5 years of RUX therapy in a cohort of patients (pts) with primary, post-polycythemia vera, or post-essential thrombocythemia MF. Methods: BM biopsies were performed at protocol-defined intervals for RUX-treated pts at baseline (BL) and at 24 months (mo) (68 pts), 48 mo (38 pts), 54 mo (23 pts), 60 mo (10 pts), or 66 mo (4 pts). To compare the effects of long-term therapy on BM fibrosis we additionally included a historical cohort of pts with primary MF treated with BAT. Samples from the BAT cohort (192 pts) were matched with those from the RUX cohort according to BM morphology at BL. Analysis in the RUX cohort included immunohistochemical assessment of therapy-induced changes by applying specific antibodies (CD61 – megakaryocytes [MEG]; CD68 – macrophages [MAC]; MUM1 – plasma cells [PLC]). Changes in these parameters were determined by consensus after independent blinded review by 3 pathologists (HMK/JT/CBR). Results were categorized as improvement, stabilization, or worsening from BL. Changes in serum levels of 73 cytokines (BL vs 4 weeks) were available in 48 (of the 68; 71%) pts of the RUX cohort. Logarithmic transformation was applied to both BL and week 4 cytokine values, and a stepwise logistic regression method was implemented to identify significant predictors. A composite variable was constructed that reflects a linear combination of the most important predictors using the slope from the logistic analysis as the coefficients. ROC curves with the status of BM response as the dependent variable were generated and the area under the curve (AUC) was calculated as a measure of accuracy. Results: In line with previous results, the odds for improvement or stabilization of BM fibrosis were greater with RUX at all time points, whereas the odds of worsening were markedly reduced with RUX vs BAT. Improvement or stabilization of BM fibrosis with RUX was associated with concordant changes in both collagen deposition and osteosclerosis. As an indicator of therapy-induced reduction in the BM inflammatory stromal reaction, in more than 70% of pts a decrease in the amount of PLC was observed. In 48% of patients, RUX induced a reduction of MAC, while in 39% of cases their number remained unchanged. MEG frequency was reduced in 52% of cases post–RUX therapy, while an increase was observed in only 6.8% of samples. Furthermore, MEG atypia was reduced in 37% of cases, while in 55% of patients a stabilization effect of therapy was seen for this parameter. Multivariate regression identified 10 cytokines that strongly correlated with morphologic outcomes with different weighting factors for each of the predictive equations: CRP: C-reactive protein, IL-10: Interleukin 10, MDC: Macrophage- derived cytokine, SCF: Stem cell factor, TNFα: Tumor necrosis factor alpha, ApoA1: Apolipoprotein A1, EOT: Eotaxin, Hp: Haptoglobin, IgE: Immunoglobulin E, TIMP1: Tissue inhibitor of metalloproteinase-1. In all pts tested RUX induced a significant change of these identified cytokines by week 4. Individual changes in parameters of BM morphology were strongly associated with corresponding changes in cytokine levels. Decrease of BM fibrosis at 24 mo was strongly associated with reduced cytokine levels (AUC=0.85939, p=0.0134). Additionally, decreased frequencies of MEG, PLC, and MAC showed significant correlations with RUX-induced modulation of cytokines (MEG: AUC=0.942572, p=0.0176; PLC: AUC=0.838135, p=0.0331; MAC: AUC=0.965495, p=0.0033). Conclusions: These results demonstrate that long-term RUX therapy, unlike BAT, causes a marked modulation of the BM cellular microenvironment. The effect observed with RUX was seen across all aspects of the fibrotic process including the inflammatory BM stromal reaction associated with MF. The complex relationships between improvement of the BM microenvironment and RUX-dependent effects on inflammatory cytokines reinforce previous observations suggesting that sustained JAK inhibition may be disease-modifying in MF. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria. Thiele:AOP Orphan Pharmaceuticals: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Consultancy, Honoraria. Sun:Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

Exploratory analysis of the effect of ruxolitinib on bone marrow morphology in patients with myelofibrosis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7030-7030 ◽  
Author(s):  
Hans-Michael Kvasnicka ◽  
Juergen Thiele ◽  
Carlos E. Bueso-Ramos ◽  
Kevin Hou ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Exploratory Analysis ◽  
World Health ◽  
Cancer Center ◽  
Jak2 Inhibitor ◽  
Comparable Effect ◽  
Md Anderson ◽  
Health Organization ◽  
Clinical Trial Information

7030 Background: Myelofibrosis(MF) is characterized by splenomegaly, burdensome symptoms, progressive bone marrow (BM) fibrosis, and shortened survival. Ruxolitinib (Rux), an oral, FDA-approved JAK1/JAK2 inhibitor, has demonstrated improvements in spleen volume, symptoms, and survival in patients (pts) with MF. This study was conducted to explore possible effects of long-term Rux treatment on BM morphology in MF. Methods: Trephine biopsies were obtained at baseline, 24 (67 pts), and 48 (17 pts) months (mo) from the cohort of MF patients treated at MD Anderson Cancer Center who participated in a phase I/II trial of Rux (NCT00509899). The clinical outcomes from this trial have been published previously [Verstovsek, NEJM 2010]. Two of the authors (JT and HMK) independently evaluated the World Health Organization (WHO)-defined BM fibrosis grade (0-3). Reviewers were blinded to pts characteristics and outcomes and consensus decided discordant scores. For demonstrative purposes, WHO BM fibrosis grading was also determined for a control cohort of pts treated with hydroxyurea (HU) for 24 (31 pts) and 48 (20 pts) mo. Changes in BM fibrosis grade vs. baseline were calculated for 24 and 48 mo, and categorized as improvement, stabilization, and worsening for each patient. Results: A higher percentage of Rux-treated pts showed stabilization or improvement of BM fibrosis at both 24 and 48 mo than the HU-treated pts. Worsening was greater in the HU-treated cohort at both time points. Conclusions: This exploratory analysis of long-term exposure to Rux in MF provides the first indication that JAK inhibitor therapy may be able to meaningfully retard advancement of BM fibrosis. A comparable effect was not seen with long-term HU therapy. Additional research is needed to further elucidate these findings. Clinical trial information: NCT00509899. [Table: see text]

scholarly journals Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls

Blood ◽  
2012 ◽  
Vol 120 (6) ◽  
pp. 1202-1209 ◽  
Author(s):  
Srdan Verstovsek ◽  
Hagop M. Kantarjian ◽  
Zeev Estrov ◽  
Jorge E. Cortes ◽  
Deborah A. Thomas ◽  
...  
Keyword(s):  
High Risk ◽  
Phase 1 ◽  
Cancer Center ◽  
Term Therapy ◽  
Long Term Outcomes ◽  
Jak2 Inhibitor ◽  
Significant Difference ◽  
Md Anderson ◽  
Long Term Therapy

Abstract Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit.

Final Results From the Phase 2 Continuation Study of the Lenalidomide and Azacitidine Combination in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 607-607 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Rami S. Komrokji ◽  
Jeffrey E. Lancet ◽  
Ramon V. Tiu ◽  
Anjali S. Advani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Neutrophil Count ◽  
Research Funding ◽  
Phase 1 ◽  
Injection Site Reaction ◽  
World Health ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Bone Marrow Biopsies ◽  
Phase 2 Trial

Abstract Abstract 607 Background: Lenalidomide (LEN) and azacitidine (AZA) have activity in lower- and higher-risk MDS patients (pts), where both microenvironment and cell regulatory mechanisms play a role. The LEN/AZA combination was well-tolerated in the Phase 1 study (Sekeres JCO 2010) that established Phase 2 dosing, with an overall response rate (ORR) of 67%. Methods: The primary objectives for this multicenter, Phase 2 trial were to determine the efficacy and safety of combination therapy, with AZA 75mg/m2 daily × 5 days, and LEN 10mg daily × 21 days of a 28-day cycle (maximum of 7 cycles), in pts with higher-risk MDS (IPSS score ≥1.5, or World Health Organization (WHO) classification with ≥5% myeloblasts) not previously treated with AZA or LEN. Adverse Events (AEs) were assessed per NCI CTC v.3.0, with median decrease in absolute neutrophil count (ANC) or platelets (plt) calculated for the first 8 weeks of therapy. Subjects were enrolled to the Phase 1 study from 5/05 through 5/08, and to the Phase 2 continuation from 3/09 through 4/11, with results reported through 7/11. Bone marrow biopsies were performed after the 4th and 7th cycles, and pts could continue on AZA monotherapy off-study. Responses were assessed per modified International Working Group criteria as complete or partial response (CR, PR), or hematologic improvement (HI), and validated centrally. Time to progression was from date of CR, and overall survival (OS) from date of study enrollment. Results: A total of 36 pts were enrolled at 3 centers (18 Phase 1, 18 Phase 2); median age was 68 years (range 47–78), 13 pts (36%) were female, median interval from diagnosis was 8 weeks (range, 2–106), and median follow-up was 15 months (range 2–60). Prior MDS therapies included growth factors (19%), immunosuppressants (14%), and chemotherapy (17%). Median baseline hemoglobin was 9.7 g/dL, platelet count 65 k/uL, neutrophil count 840 k/uL, erythropoietin level 108 MIU/mL, and bone marrow blast percentage was 11%. IPSS categories were Int-1 (5 pts), Int-2 (20 pts), and High (11 pts); 8 pts had RAEB-1, 21 had RAEB-2, and 3 had CMML. Only 1 pt had a chromosome 5q deletion. Pts received a median of 5 cycles of therapy on-study. Grade 3/4 non-hematologic AEs (related or unrelated) included cardiac (11%), febrile neutropenia (31%), other infection (8%), pulmonary (11%), vascular access-related thrombosis (6%), CNS hemorrhage (6%), or other (11%). Three pts (8%) died while on-study. The most common grade ≤2, non-hematologic AEs related to treatment included constipation (47%), dermatologic (rash or injection site reaction) (44%), fatigue (39%), diarrhea (39%), nausea (19%), dizziness (19%), and dyspnea (19%). Median decrease from baseline in ANC was 35% and in plts was 18%. Of 35 patients evaluable, the ORR was 71%: 14 pts (40%) had a CR and 11 (31%) had HI, of whom 3 had bi- or tri-lineage HI. Median time to response was 3 months (range, 1–7). Three patients had progressive disease while on-study. Among pts achieving a CR, 7 (50%) continue to receive therapy; median age was 68 years (range, 50–76); IPSS was Int-1 (n=3), Int-2 (n=9), and High (n=2); WHO was RAEB-1 (n=5) and RAEB-2 (n=9); cytogenetic profiles were: 9 (64%) normal; 1 (7%) del (5q); 1 (7%) +8, 1 (7%) −7, 1 (7%) complex, and 1 (7%) unknown; median CR duration at last study assessment was 16 months (range, 3–36) and median OS at last assessment among CR pts was 27 months (range, 7–55). Seven CR pts (50%) evolved to AML a median of 20 months from achieving CR (range, 9–31); 10 (71%) remain alive at last study assessment. Conclusions: The LEN/AZA combination is well-tolerated and highly active in treating higher-risk MDS. The ORR seen in the Phase 1 study was supported by Phase 2 data, with good OS, even among progressing pts. Subsequent randomized studies will compare the LEN/AZA combination to AZA monotherapy and other AZA-based combinations. Disclosures: Sekeres: Celgene: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of lenalidomide, wapproved for lower-risk del(5q), will be discussed in higher-risk patients with MDS. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy. Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paula A. Lengerke Diaz ◽  
Michael Y. Choi ◽  
Eider F. Moreno Cortes ◽  
Jose V. Forero ◽  
Juliana Velez-Lujan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (&gt;5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as &lt;10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

scholarly journals The Necessary for Long-Term Follow-up of Mutated Genes and Clonal Evolutions in Multiple Myeloma Combined with cfDNA Assay

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5515-5515
Author(s):  
Yuko Mishima ◽  
Yuji Mishima ◽  
Masahiro Yokoyama ◽  
Noriko Nishimura ◽  
Yoshiharu Kusano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Genomic Dna ◽  
Research Funding ◽  
Somatic Mutations ◽  
Clinical Course ◽  
Bone Marrow Aspiration ◽  
Long Term Follow Up

Introduction)Somatic mutations in multiple myeloma (MM) are strongly related to the clinical outcome and clonal evolution over the clinical course, and are a major problem. From a clinical viewpoint, although numerous novel drugs have been utilized, achieving long-lasting and complete remission remains difficult. Recent studies have elucidated the mutated genes using next-generation sequencing, and have examined how clonal change can be acquired in myeloma. In this study, we traced the transition of the somatic mutations of bone marrow tumor cells in patients with MM over a long-term follow-up. Furthermore, we compared the somatic mutations found in serum cell-free DNA (cfDNA) and mutated genes obtained from bone marrow myeloma cells. Material and Methods)Patients diagnosed with multiple myeloma who provided written informed consent to participate in the study were enrolled. Patients were treated by immuno-chemotherapy with or without radiation between 2000 and 2017 at our institute. Bone marrow aspiration and biopsy were performed at the time of diagnosis and upon disease progression. Around the time of bone marrow aspiration, serum was obtained from a peripheral blood sample for cfDNA analysis. Myeloma cells were separated from bone marrow samples with MicroBeads of CD138 antibody and genomic DNA was extracted. The peripheral blood samples derived from myeloma patients. The cfDNA was extracted from the serum using a Maxwell RSC cfDNA Plasma kit. Using genomic DNA derived from cfDNA and bone marrow, multiplex polymerase chain reaction (PCR) was performed, and a sequence library was then constructed with an Ion Custom Amplicon panel. The panel for the sequence library was designed using an Ion AmpliSeq DesignerTM. 126 targeted genes were selected. The genomes were sequenced using the Ion ProtonTM System. This protocol was approved by the institutional review board and the Genomic Review Board of the Japanese Foundation for Cancer Research. Result)We followed 7 patients' long term-clinical course and the transition of mutations (8.5 year average). The expression of myeloma driver genes, such as RAS, BRAF, and MYC, were not critical. We did, however, detect a relationship between an increase in the dominant mutated gene, such as TP53, DIS3, FAM46C, KDM6B, and EGR1 and poor prognosis in patients with myeloma. Next, we calculated the cfDNA concentrations from 34 cases. The cfDNA concentrations were significantly higher than 10 control cases (average 62.0 ng/mL (0-200 ng/mL) and 8.18 ng/mL (4.3-14.1 ng/mL), P=0.0046). The 2.5 year-progression free survival (PFS) during the first treatment of MM were tend to be poorer in the group with cfDNA>50 ng/mL (72.9%) than the group with cfDNA<50 ng/mL(25.9%), however there are no statistical significance (P = 0.15).We caluculated concordance rate of derived mutations from bone marrow MM cells and cfDNA in 7 cases. The somatic mutations found in serum cell-free DNA (cfDNA) and bone marrow MM cells were determined the correlation coefficients. However, there are few difference expression pattern in each source. In cfDNA assay, CREEP, EGR1, HDAC4, HDAC6, and JMJD1C were highly expressed as 57.1% (4/7) - 85.7% (6/7), and these results were almost the same as those for bone marrow MM cells. On the other hand, KDM1A (85.7%), PI3KCD (71.4%), and KDM3B (57.1%) were highly detected in cfDNA, although those were not frequently expressed in bone marrow. Discussion)Our data demonstrate the importance of the long-term follow-up of somatic mutations during the clinical course of myeloma. Serum cfDNA is a useful alternative source for detecting somatic mutations in MM patients during long-term follow-up. Disclosures Mishima: Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Yokoyama:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Nishimura:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy; Celgene K.K.: Honoraria. Hatake:Celgene K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Takeda Pharmaceutical Co.,Ltd.: Honoraria. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria.

Mortality After Cure of Testicular Seminoma

2004 ◽  
Vol 22 (4) ◽  
pp. 640-647 ◽  
Author(s):  
Gunar K. Zagars ◽  
Matthew T. Ballo ◽  
Andrew K. Lee ◽  
Sara S. Strom
Keyword(s):  
Observation Interval ◽  
Cancer Center ◽  
Standardized Mortality Ratio ◽  
Testicular Seminoma ◽  
Term Survival ◽  
Risk Of Death ◽  
Cancer Management ◽  
Long Term Survivors

Purpose To determine the incidence of potentially treatment-related mortality in long-term survivors of testicular seminoma treated by orchiectomy and radiation therapy (XRT). Patients and Methods From all 477 men with stage I or II testicular seminoma treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) with postorchiectomy megavoltage XRT between 1951 and 1999, 453 never sustained relapse of their disease. Long-term survival for these 453 men was evaluated with the person-years method to determine the standardized mortality ratio (SMR). SMRs were calculated for all causes of death, cardiac deaths, and cancer deaths using standard US data for males. Results After a median follow-up of 13.3 years, the 10-, 20-, 30-, and 40-year actuarial survival rates were 93%, 79%, 59%, and 26%, respectively. The all-cause SMR over the entire observation interval was 1.59 (99% CI, 1.21 to 2.04). The SMR was not excessive for the first 15 years of follow-up: SMR, 1.30 (95% CI, 0.93 to 1.77); but beyond 15 years the SMR was 1.85 (99% CI, 1.30 to 2.55). The overall cardiac-specific SMR was 1.61 (95% CI, 1.21 to 2.24). The cardiac SMR was significantly elevated only beyond 15 years (P < .01). The overall cancer-specific SMR was 1.91 (99% CI, 1.14 to 2.98). The cancer SMR was also significant only after 15 years of follow-up (P < .01). An increased mortality was evident in patients treated with and without mediastinal XRT. Conclusion Long-term survivors of seminoma treated with postorchiectomy XRT are at significant excess risk of death as a result of cardiac disease or second cancer. Management strategies that minimize these risks but maintain the excellent hitherto observed cure rates need to be actively pursued.

scholarly journals Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up

Blood ◽  
2018 ◽  
Vol 131 (21) ◽  
pp. 2331-2334 ◽  
Author(s):  
Robert J. Kreitman ◽  
Martin S. Tallman ◽  
Tadeusz Robak ◽  
Steven Coutre ◽  
Wyndham H. Wilson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Aspirate ◽  
Phase 1 ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Key Points ◽  
Long Term Follow Up ◽  
Minimal Residual

Key Points Moxetumomab pasudotox eradicated HCL MRD in >50% of CRs, even by the most sensitive measure, bone marrow aspirate flow cytometry. Elimination of MRD was significantly associated with prolonged CR duration.

Phase 1/2 Study of Elotuzumab in Combination with Bortezomib in Patients with Multiple Myeloma with One to Three Prior Therapies: Interim Results.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3876-3876 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
William Bensinger ◽  
David Siegel ◽  
Todd M. Zimmerman ◽  
Jan M. Van Tornout ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Surface Glycoprotein ◽  
Advisory Committees ◽  
Cell Surface Glycoprotein

Abstract Abstract 3876 Poster Board III-812 Background Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). In mouse xenograft models of MM, elotuzumab demonstrated significantly enhanced anti-tumor activity when combined with bortezomib compared to bortezomib alone (Van Rhee et al., Mol. Cancer Ther., in press, 2009). This phase 1/2 trial will determine the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and clinical response of elotuzumab in combination with bortezomib in patients with relapsed MM following 1-3 prior therapies. Methods The study consists of 4 escalating cohorts of elotuzumab (2.5 mg/kg to 20 mg/kg) administered on Days 1 and 11 and bortezomib (1.3 mg/m2) administered on Days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease at the end of Cycle 2 or 3 also receive oral dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each subsequent cycle. Patients with stable disease or better at the end of 4 cycles will continue treatment for 6 or more cycles unless withdrawn earlier due to unexpected toxicity or disease progression. Key entry criteria: age ≥ 18 years; confirmed diagnosis of MM and documentation of 1 to 3 prior therapies; measurable disease M-protein component in serum and/or in urine; and no prior bortezomib treatment within 2 weeks of first dose. Results To date, a total of 16 MM patients with a median age of 64 years have been enrolled in the study. The median time from initial diagnosis of MM was 3.5 years and patients had received a median of 2 prior MM treatments. Patients have been treated in four cohorts; 3 each in 2.5, 5 and 10 mg/kg elotuzumab cohorts, and 7 in the 20 mg/kg elotuzumab cohort. No dose limiting toxicity (DLT) was observed during the first cycle of the study and the MTD was not established. Five SAEs have been reported in four patients in later treatment cycles; two events, chest pain and gastroenteritis, occurring in one patient, were considered elotuzumab-related. Other SAEs include grade 3 sepsis, vomiting, pneumonia and grade 2 dehydration. The most common AEs reported include Grade 1-3 diarrhea, constipation, nausea, fatigue, thrombocytopenia, neutropenia, anemia and peripheral neuropathy. The best clinical response (EBMT criteria) for the 16 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis suggests a serum half-life of 10-11 days at higher doses (10 and 20 mg/kg). Preliminary analysis of peripheral blood mononuclear cells and bone marrow of patients on study indicates that objective responses in the study correlate well with complete saturation of CS1 sites by elotuzumab on bone marrow plasma and NK cells. Conclusions The combination of elotuzumab with bortezomib has a manageable adverse event profile and shows promising preliminary efficacy with ≥PR in 44% and ≥MR in 75% of all enrolled patients. Accrual is ongoing in the expanded 20 mg/kg cohort. Updated safety, efficacy, and PK data will be presented at the meeting. Disclosures: Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib in combination with elotuzumab for the treatment of relapsed/refractory multiple myeloma. Bensinger:Millennium: Membership on an entity's Board of Directors or advisory committees. Siegel:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman:Millennium: Speakers Bureau; Centecor: Speakers Bureau. Van Tornout:BMS: Employment. Zhao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2455-2455 ◽  
Author(s):  
Thomas J. Kipps ◽  
William G. Wierda ◽  
Jeffrey A. Jones ◽  
Lode J. Swinnen ◽  
Jianning Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Phase 2 ◽  
Anti Tumor Activity

Abstract Abstract 2455 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50 ≤ 1μM) against T and B lymphoid malignancies that over-express Bcl-2. A phase 1 trial demonstrated oral navitoclax monotherapy to be well-tolerated and to have anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). However, thrombocytopenia (TCP) was the dose-limiting toxicity (DLT). Phase 3 studies showed improved outcomes in CLL pts with the fludarabine/cyclophosphamide/rituximab (FCR) combination, and a phase 2 trial showed bendamustine/rituximab (BR) to be effective for pts with relapsed or refractory CLL. Navitoclax enhanced R (monotherapy and in combination with chemotherapy) efficacy in preclinical models of B-cell lymphoma. Methods: This is an ongoing, international, phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of oral navitoclax in combination with FCR (Arm A) or BR (Arm B) in pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥100/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. After obtaining informed consent, pts were assigned to Arm A or Arm B based on physician preference, each consisting of 28-day dose-escalation cycles with once-daily, pre-infusion, navitoclax treatment on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Navitoclax starting dose was 110 mg daily. Dose escalation to the next cohort (200 mg) was according to a continuous reassessment model. Tumor responses were evaluated using NCI-WG 1996 criteria. Pts could continue on navitoclax therapy for 1 yr in the absence of progressive disease or significant toxicity. Results: As of July 2010, 7 pts enrolled in the initially prioritized Arm B (BR+navitoclax); all completed the first cohort of 110 mg (median age 60 yr [range 55–72]). Study sites are currently enrolling pts in Arm A (FCR+navitoclax); 2 pts have enrolled to date. The median number of prior therapies was 2 (range 1–7). One pt had a DLT of elevated AST (Arm B, 110 mg cohort) and 1 pt had a DLT of neutropenic fever (Arm A, 110 mg cohort). In Arm B, neither TCP nor neutropenia have been DLTs. For the 7 pts with navitoclax-related AEs, the most common were diarrhea (3 pts), nausea (5 pts), and fatigue (3 pts). Seven pts remain on study; 2 pts discontinued due to disease progression and 2 withdrew per physician preference. In Arm B, preliminary antitumor best responses were assessable in 4 pts who received 2 cycles; 1 CRi in a pt with del17p- (based on lymph node [LN] response and no morphologic evidence of CLL in the bone marrow), 2 unconfirmed CRs (based on LN response and no bone marrow at this time), and 1 PR in a pt with del17p- (this pt subsequently received an allogeneic stem cell transplant). Preliminary PK results for the Arm B 110 mg cohort indicated that navitoclax PK was similar in Cycle 1 (navitoclax+BR) and Cycle 2 (navitoclax alone), and appeared comparable to PK in the navitoclax monotherapy study. Conclusions: Early results show that the combination of navitoclax with BR is well-tolerated, without DLTs of TCP or neutropenia, and show evidence of anti-tumor activity. Data are limited in the FCR portion of the study. The maximum tolerated dose of navitoclax has not been reached. Accrual is ongoing and following completion of the dose-escalation components of this study, expanded cohorts of pts will be assessed using the recommended phase 2 dose of navitoclax to further assess the tolerability and dose, and to continue to explore for efficacy signals in combinations. Preliminary data in combination with BR are encouraging. Disclosures: Kipps: Abbott Laboratories: Research Funding; Genentech/Roche: Research Funding. Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Swinnen: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yang: Abbott: Employment. Cui: Abbott: Employment. Busman: Abbott: Employment. Krivoshik: Abbott: Employment. Enschede: Abbott: Employment. Humerickhouse: Abbott: Employment.

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