Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Final Results of the Z-MARK Study

Abstract Abstract 4077 Introduction: Treatment with zoledronic acid (ZOL, 4mg) has proven effective for reducing the risk of skeletal-related events (SREs) in patients (pts) with multiple myeloma (MM), with a SRE incidence rate as low as 27% after 3.7 years' median follow-up (Morgan G, et al. Lancet Oncology 2011;12:743-52). Pts with normal bone metabolism may not require as intense a treatment schedule as pts with accelerated bone turnover. The Z-MARK study evaluated if pts with 1–2 years of prior intravenous (IV) bisphosphonate (BP) therapy can be treated safely long-term with less-frequent ZOL dosing based on bone turnover markers. Methods: MM pts (N=121) who started IVBP therapy (ZOL or pamidronate) 1–2 years before enrollment and received ≥4 prior doses, with baseline calculated creatinine clearance (CrCl) of ≥30 mL/min, were enrolled. Pts received 4mg IV ZOL every (q) 4 or 12 weeks (wk) based on their most recent urinary N-telopeptide of type I collagen (uNTX) levels (q4 wk if uNTX ≥50 nmol/mmol Cr, q12 wk if uNTX <50 nmol/mmol Cr). Pts who developed a SRE or had disease progression requiring a change in MM therapy on study were treated q4 wk thereafter regardless of uNTX levels. The study's primary endpoint was the proportion of pts who experienced ≥1 SRE during study Year 1. Group A (ZOL q12 wk only, N=79) is compared with Group B (all others, N=42). Results: Of 121 pts enrolled, 52 discontinued early: 29 (36.7%) in A and 23 (54.8%) in B. Median time to discontinuation was ∼20 months (mo) in A and ∼24 mo in B. Median time on ZOL on study was 22.5 mo for A and 20.8 mo for B. The mean age was 63.8 years (range, 34–90) with approximately 1:1 male:female ratio. By International Staging System criteria, 81.0% in A and 69.1% in B were Stage I/II, while 15.2% and 19.0% were Stage III. Median time from initial MM diagnosis to enrollment was 18.4 mo in A and 18.6 mo in B. A majority of pts in both groups had ≥1 osteolytic lesions at enrollment (A, 65.8%; B, 76.2%). The median duration of prior IVBP therapy was 13.8 mo in A and 14.4 mo in B. At enrollment, 72.2% in A and 78.6% in B had ≥1 SRE. The baseline mean (standard deviation) for uNTX and calculated CrCl was 19.88 (8.8) nmol/mmol Cr, and 85.1 (31.8) mL/min in A and 24.1 (15.6) nmol/mmol Cr and 84.3 (40.0) mL/min in B. Four pts started ZOL at q4 wk vs 117 pts at q12 wk based on uNTX at study entry. Of 117 pts assigned to q12-wk dosing, 79 stayed on schedule throughout the study; 38 pts switched to q4 wk (14 for increased uNTX, 4 for SREs, and 20 for disease progression). Only 7 pts (5.8%; all in A) had a SRE in study Year 1 (3 pathologic fractures, 3 spinal cord compressions, 4 radiation to bone, 1 surgery to bone, 1 hypercalcemia of malignancy). In Year 2, only 5 pts (4.1%) had a SRE (1 pathologic fracture, 4 radiation to bone). Baseline uNTX (low: <28, high: ≥28) was predictive of SREs (hazard ratio=3.1, P=.06). Treatment was well-tolerated. The most common AEs were fatigue (26.4%), upper respiratory tract infection (24%), diarrhea (21.5%), pneumonia (21.5%), cough (20.7%), pyrexia (18.2%), arthralgia (17.4%), and nausea (17.4%); none were attributed to ZOL. Except for arthralgia, the incidence of these AEs was higher in B vs A. Serious AEs were reported in 29.1% in A and 59.5% in B. Overall, 19.8% of pts (15.2% A, 28.6% B) had an AE leading to ZOL discontinuation. At 48 wk, the median percentage change in uNTX was –13.3% in A and 0% in B. No change in the median serum Cr was observed in either group at 48 wk. Four deaths (2 from progression of MM, 1 from pneumonia, 1 unknown) were reported on study (not suspected to be related to ZOL). Four reports of osteonecrosis of the jaw (ONJ) were suspected to be related to ZOL (all in A, q12-wk dosing) at 22.2 mo median follow-up. Conclusions: The final Z-MARK results show that bone marker-directed dosing is feasible and safe in pts with 1–2 years of prior IVBP therapy. The low incidence of SREs on study shows that less-frequent IVBP dosing beyond 1–2 years continues to reduce the SRE risk and may reflect changing treatment patterns for MM that include therapies with bone protective effects. Baseline uNTX (≥28 nmol/mmol Cr) trended toward significance for predicting SREs. Finally, this study, which prospectively evaluated ONJ beyond 3 years, demonstrated an incidence rate of 3.3%. Further studies and additional follow-up are needed to determine the potential predictive value and long-term benefits of bone marker-directed ZOL dosing in MM pts after standard IVBP treatment. Disclosures: Raje: Amgen: Research Funding; Acetylon: Research Funding; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Eli-Lilly: Research Funding; Novartis: Consultancy. Off Label Use: Zoledronic acid (4 mg every 3–4 weeks) is indicated for the treatment of patients with multiple myeloma and patients with bone metastases from solid tumors. Vescio:Novartis Pharmaceuticals Corporation: Speakers Bureau. Hadala:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis: Equity Ownership; Novartis: Employment. Ericson:Novartis Pharmaceuticals Corporation: Employment, Stocks Other. Anderson:Novartis Pharmaceuticals Corporation: Consultancy.

Download Full-text

Bone Marker Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Primary Analysis Results of the Z-MARK Study

Blood ◽

10.1182/blood.v118.21.5122.5122 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5122-5122

Author(s):

Noopur Raje ◽

Robert Vescio ◽

Charles W. Montgomery ◽

Ramakrishnan Parameswaran ◽

Diep Tran ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Bone Marker ◽

Primary Analysis ◽

Employment Equity ◽

Advisory Committees ◽

Skeletal Complications ◽

Equity Ownership

Abstract Abstract 5122 Background: Standard monthly infusions of 4 mg zoledronic acid (ZOL) have been proven effective at reducing the risk of skeletal complications in patients with multiple myeloma (MM). It is hypothesized that patients with normal bone metabolism may not require as intense a treatment schedule as patients with accelerated bone resorption. The Z-MARK study evaluates whether patients who have been treated with IV bisphosphonates (BP) for 1–2 years can safely be treated long-term with less frequent dosing of ZOL based on bone turnover markers. Materials and Methods: MM patients (N=121) who had started standard monthly IV BP (ZOL or pamidronate, PAM) 1–2 years prior to enrollment and received ≥4 prior doses, with baseline calculated creatinine clearance (CrCl) of ≥30 mL/min, were enrolled. Patients received 4mg IV ZOL q4 or q12 weeks based on their most recent urine NTX (uNTX) measurement (uNTX≥50 nmol/mmol Cr - infusion q4 weeks, uNTX<50 nmol/mmol Cr - infusion q12 weeks). Patients who developed a skeletal related event (SRE) or had disease progression requiring a change in their MM therapy while on study were treated q4 weeks thereafter regardless of their uNTX values. The primary endpoint of the study is the proportion of patients who experience at least one SRE during study Year 1. This primary analysis (PA) includes all enrolled patients who completed study Year 1 or have discontinued from the study. Results are summarized by Group A (consisting of patients receiving ZOL q12 weeks only, N=83) and all others in Group B (N=38). Results: As of the May 9, 2011 data cut-off date, 31.3% (9.6% due to AEs, 14.5% withdrew consent, and 7.2% due to other reasons) in A and 36.8% (15.8% due to AEs, 10.5% withdrew consent, and 10.5% due to other reasons) in B discontinued early. The mean age was 63.8 years, with approximately 1:1 male/female ratio. The baseline mean (SD) for uNTX and calculated CrCl was 21.3 (11.8) nmol/mmol Cr and 84.8 (34.7) mL/min, respectively. Based on the International Staging System, 79.5% of the patients were stage I or II and 14.5% were stage III at enrollment in A. The same in B were 71.1% and 21.1%. The median time from initial MM diagnosis to enrollment was 18.4 months in both groups. In A, 67.5% had ≥1 osteolytic lesions and of these 37.5% had >6; in B, 73.7% had ≥1 and of these 42.9% had >6. In A, 83.1% had received ZOL only, 13.3% had received PAM only; in B, 92.1% had received ZOL only and 2.6% had received PAM only prior to enrollment. The median duration of prior BP therapy was 13.8 in A and 14.8 months in B. In A, 73.5% had ≥1 SREs at enrollment; in B the same was 76.3%. Four patients started study ZOL treatment on the q4-weeks dosing schedule and 117 patients started on the q12-weeks schedule (based on uNTX values at study entry). Thirty four of 117 patients assigned to q12-week dosing were switched to q4 weeks (14 due to increased uNTX, 4 due to SREs, and 16 due to disease progression). In study Year 1, no patient in A had any SRE while 7 patients in B had SREs (3 pathologic fractures, 3 spinal cord compressions, 4 radiations to bone, 1 surgery to bone, 1 hypercalcemia of malignancy). Only 5.8% of patients had any SRE in the first year. In A, 90.4% of patients had any adverse event (AE) while it was 100% in B. The most common AEs were upper respiratory tract infection (23.1%), fatigue (23.1%), cough (19%), diarrhea (19%), pneumonia (18.2%), pyrexia (18.2%), arthralgia (16.5%) and nausea (15.7%). The percentage of patients with any serious AE was 26.5 in A and 57.9 in B. Overall, 14.9% (12.0% in A, 21.1% in B) of patients had an AE leading to ZOL discontinuation. At Week 48, the median % change in uNTX was −11.1 in A and 12.5 in B. For serum Cr, no change in the median was observed in either group at Week 48. One death was reported on study (not suspected to be related to ZOL). There were 3 reports of osteonecrosis of the jaw (ONJ) in A, suspected to be related to ZOL, and no report of ONJ in B; the median time on ZOL was 17.0 months for A and 17.3 months for B. Discussion: These Z-MARK PA results show that bone marker directed dosing is feasible in patients who had 1–2 years of prior IV BP therapy. The low number of SREs observed within 1 year of study follow up is possibly due to the persistent protective effects from IV BP treatment prior to study entry and on study. Additional follow up is needed to determine the potential predictive value and the long-term benefits of bone marker directed dosing of ZOL in MM patients following standard IV BP treatment. Disclosures: Raje: Acetylon: Research Funding; Astra Zeneca: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Zoledronic acid: Studying alternate dosing schedule in multiple myeloma(bone marker directed dosing). Vescio:Novartis Pharmaceuticals Corporation: Speakers Bureau. Tran:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis: Employment, Equity Ownership. Argonza-Aviles:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Anderson:Novartis Pharmaceuticals Corporation: Consultancy.

Download Full-text

Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽

10.1182/blood-2019-129274 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2352-2352

Author(s):

Tomas Jose Gonzalez-Lopez ◽

Fernando Fernandez-Fuertes ◽

Maria Cristina Pascual Izquierdo ◽

Isabel Caparros ◽

Silvia Bernat ◽

...

Keyword(s):

Platelet Count ◽

Median Time ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Previous Treatment ◽

Complete Response ◽

Platelet Response ◽

Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

Download Full-text

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

Blood ◽

10.1182/blood-2020-143473 ◽

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 (>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 <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.

Download Full-text

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

Blood ◽

10.1182/blood-2019-122977 ◽

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.

Download Full-text

Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽

10.1182/blood.v120.21.3785.3785 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3785-3785 ◽

Cited By ~ 1

Author(s):

H. Jean Khoury ◽

Carlo Gambacorti-Passerini ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

David Marin ◽

...

Keyword(s):

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Disease Progression ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Download Full-text

Long-Term Outcome of Patients with Marginal Zone Non-Hodgkin Lymphoma (MZL) Treated with Yttrium-90 Ibritumomab Tiuxetan: The Mayo Clinic Experience

Blood ◽

10.1182/blood-2019-130384 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1544-1544

Author(s):

Muhamad Alhaj Moustafa ◽

Ricardo Parrondo ◽

Gregory Wiseman ◽

Jennifer Peterson ◽

Thomas E. Witzig ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Low Grade ◽

Ibritumomab Tiuxetan ◽

Term Outcome ◽

Long Term Outcome ◽

Grade 3 ◽

Yttrium 90

Background MZL is a low-grade non-Hodgkin's lymphoma (NHL) which involves lymph nodes, extranodal sites, or spleen. It is sensitive to radiation therapy, which is used in localized disease with curative intent. Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) that targets CD20. It is approved for relapsed/refractory low grade and follicular NHL. The data on its use in MZL is limited. We present long-term outcome of the largest reported cohort of MZL patients who received (90)Y-IT. Methods Medical records of patients who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2004 and December 2018 were analyzed. We selected patients with MZL and reviewed clinical data including age, gender, MZL type, clinical stage (Ann Arbor Staging System), treatment response, (90)Y-IT related adverse effects (AEs), as well as lymphoma and treatment related events. All patients received (90)Y-IT according to the standard treatment guidelines. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Twenty-one patients were identified (Table 1). The median age at diagnosis was 60 years (range, 11-81) and 71% (15/21) were female. 52% (11/21) were previously-untreated (UMZL) while 48% (10/21) were relapsed (RMZL). The median number of pretreatments in RMZL patients was 2 (range, 1-3). ECOG performance status at the time of treatment was 0 in 90% (19/21) and 1 in 10% (2/21). 62% (13/21) were stage III/IV disease at the time of (90)Y-IT therapy. The median follow-up was 8.5 years (95% CI; 4.5, 12.4); 17 (81%) patients remain alive. The ORR was 91% (19/21) with the two non-responders being in the RMZL group. The CR rate was 81% (17/21) and 65% (11/17) remain in CR at a median follow-up of 5.7 years (95% CI; 1.4, 11). Nine (43%) patients had a relapse during the study period. More relapses occurred in the RMZL group (7/10; 70%) compared to (2/11; 18%) in the UMZL group. Median PFS (whole cohort) was 10 years (95% CI; 2.1, NR) and TTNT (whole cohort) was not reached (NR) (95% CI; 2.1 years, NR). Median PFS was significantly higher in UMZL group compared to RMZL group NR (95% CI; 2.5 years, NR) vs 2.1 years (95% CI; 0.17, 9.9), respectively (Figure 1-A).Median OS (whole cohort) was 19.3 years (95% CI; 8.9, 19.3) without statistical difference in between UMZL group and RMZL group NR (95% CI; NR, NR) vs 16.6 years (95% CI; 9, 19.4), respectively (Figure 1-B). None of the 11 UMZL patients died at median follow up of 4.7 years (95% CI; 1.6, 9.2). All 4 deaths were in the RMZL group with 3 dying of transformation to high-grade lymphoma at 8, 22, and 25 months post-(90)Y-IT treatment. One patient died of myelodysplastic syndrome 7.3 years post-(90)Y-IT treatment while in CR. Toxicities were primarily hematologic. Grade ³3 neutropenia was observed in 6/21 (29%) patients with median time to nadir of 48.5 days (range, 19-70) and median time to recovery to normal absolute neutrophil count of 39.5 days (range, 7-476). Grade ³3 thrombocytopenia was observed in 3 (14%) patients with median time to nadir of 35 days (range, 19-357) and median time to recovery of 21 days (range, 2-538). Grade ³3 anemia was observed in only one patient. Only two patients required transfusions and growth factor support. Non-hematologic AEs included mild to severe fatigue in 4 patients. Conclusion RIC with (90)Y-IT is efficacious and well-tolerated in patients with previously untreated as well as relapsed MZL. As expected it appears to be more efficacious in previously untreated patients. Long-term complete remission (>5 years) was observed in 52% of the study population (43% of UMZL and 9% of RMZL). Combination of efficacy, tolerability, and treatment schedule most convenient for patients makes (90)Y-IT a reasonable alternative to systemic therapy with immunotherapy, chemotherapy, or chemo-immunotherapy in management of MZL. Figure 1: (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UMZL) and patients with relapsed MZL (RMZL), (B) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UMZL patients and RMZL patients. Disclosures Tun: Curis: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: The use of Yttrium-90 ibritumomab tiuxetan as a first line treatment for marginal zone lymphoma

Download Full-text

Characteristics and Outcome of Myelofibrosis Patients on Long-Term Ruxolitinib Therapy (≥3 years)

Blood ◽

10.1182/blood-2020-142554 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 19-20

Author(s):

Lucia Masarova ◽

Prithviraj Bose ◽

Naveen Pemmaraju ◽

Lingsha Zhou ◽

Sherry A. Pierce ◽

...

Keyword(s):

High Risk ◽

Median Time ◽

Median Duration ◽

Research Funding ◽

Response To Therapy ◽

International Prognostic Scoring System ◽

Duration Of Therapy ◽

Grant Support

Introduction: The JAK1/2 inhibitor, ruxolitinib, was approved in the USA in 2011 for the treatment of patients with myelofibrosis (MF) with intermediate and high-risk IPSS score (International Prognostic Scoring System). In the approval phase 3 COMFORT 1 - 2 studies, about 50% patients were taking ruxolitinib for at least 3 years, respectively. Objective: We sought to evaluate the characteristics and outcome of MF patients on long-term ruxolitinib therapy (≥3 years) at our center. Methods: We retrospectively reviewed the charts of patients with MF who were treated with ruxolitinib for ≥3 years. Cytogenetic were classified into risks according to Gangat et all, JCO, 2011. Descriptive statistics were used for nominal and continues variables, captured at the time of ruxolitinib start. Duration of therapy and overall survival (OS) were estimated using the Kaplan-Meier method, from the start of ruxolitinib initiation until the last day of initial ruxolitinib therapy, the date of last follow-up or death, respectively. Response to therapy was according to IWG-MRT 2013 criteria. Results: Among 437 patients who initiated therapy with ruxolitinib at our center, 136 (31%) remained on therapy for ≥3 years and represent current cohort. Ninety-one patients (67%) were newly diagnosed; the remaining patients presented after a median of 28 months (range, 4-228) from MF diagnosis. Median time to initiate ruxolitinib from presentation to our center was 1 month (range, 0.3-123) for all patients. However, the time was longer for patients who presented > 3 months from MF diagnosis (median of 11.5 months; range, 3.5-123). Patient's characteristics (n = 136) at the time of ruxolitinib initiation are summarized in Table 1. Median age was 67 years (range, 32-84), and 76 (56%) of patients were males. Half of the patients had high risk IPSS score, > 80% had systemic symptoms or splenomegaly. Eighty six percent of patients had diploid or favorable karyotype. JAK2 mutation was detected in 87% of tested patients. Median duration of ruxolitinib therapy was 72 months (95% CI: 66-78). Over the median follow-up of 83 months (range, 36-174), 63 patients (46%) died. Currently, 48 (35%) patients are still on ruxolitinib; 88 discontinued therapy after a median time of 55 months (range, 47-63). By 5th and 7th year of therapy, out of 136 patients that were treated for at least 3 years, 35% and 65% percent of patients discontinued treatment. The reasons for discontinuation included allogeneic stem cell transplantation (SCT, n 5), cytopenia (n 6), progression of MF (n 38), progression to accelerate phase (n 2) or acute leukemia (n 7), patient's choice (n 11), and death (n 23: infection 4, cardiac 3, cancer 3, others 16). Overall, 101 patients (74%) achieved IWG-MRT response, represented in majority by clinical improvement (CI) in spleen (n 90, 84%) and CI in TSS (n 51, 71%), respectively. The remaining patients achieved clinical benefit not qualifying for overall IWG-MRT response. Median duration of IWG-MRT response was 55 months (95% CI: 48-63). Responses were ongoing in 29 patients (29% of initial responders) at the time of last follow-up. Median duration of therapy was 75 months (95% CI: 68-82) for responders vs 60 months (95% CI: 39-79) for non-responders, p = 0.74. Median OS from the start of ruxolitinib was 90 months (95% CI: 76-104), Figure 1. Median OS for patients who were on ruxolitinib for ≥5 years (n = 73) was 106 months (95% CI: 80-137). Univariate and multivariate analysis for factors associated with OS is shown in Table 2. After ruxolitinib discontinuation, 25 patients received subsequent treatment at our center: SCT in 6, another JAK inhibitor in 11, other investigational agents in 3, chemotherapy in 5 patients. Median OS from ruxolitinib discontinuation was 20 months (95% CI: 12-28). Conclusion: Our data with the longest follow-up of patients receiving ruxolitinib for ≥3 years confirm the long-term benefit of this therapy with a median OS approaching 8 years since ruxolitinib treatment initiation. Disclosures Bose: Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; NS Pharma: Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Celgene: Honoraria; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding.

Download Full-text

Conditional Survival Analysis of 816 Multiple Myeloma (MM) Patients Constitutes a Different Way to Provide More Specifically Determined Prognosis

Blood ◽

10.1182/blood.v126.23.2091.2091 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2091-2091

Author(s):

Maximilian Schinke ◽

Inga Promny ◽

Stefanie Hieke ◽

Johannes M. Waldschmidt ◽

Gabriele Ihorst ◽

...

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Conditional Survival ◽

Term Survival ◽

Long Term Survival ◽

Prediction Time ◽

Risk Parameters ◽

Over Time

Abstract Introduction: Disease monitoring based on genetics or other molecular markers obtained by noninvasive or minimally invasive methods will potentially allow the early detection of treatment response or disease progression in cancer patients. Investigations in order to identify prognostic factors, e.g. patient's baseline characteristics or molecular markers, contributing to long-term survival potentially provide important information for patients with multiple myeloma. Overall survival (OS) is not very informative for patients who already survived one or more years. To better characterize long-term survival respectively long-term survivors, conditional survival (CS) analyses are useful. Conditional survival (CS) describes probabilities of surviving t additional years given they survived s years and provides information, how prognosis evolves over time. We have demonstrated the use of CS in a large data set of multiple myeloma patients with long-term survival which is mandatory for the calculation of CS (Hieke,... Engelhardt, Schumacher. CCR 2015). Methods: We evaluated 816 consecutive multiple myeloma patients treated at our department from 1997 to 2011 with follow-up until the end of 2011. Patients' data were assessed via electronic medical record (EMR) retrieval within an innovative research data warehouse. Our platform, the University of Freiburg Translational Research Integrated Database Environment (U-RIDE), acquires and stores all patient data contained in the EMR at our hospital and provides immediate advanced text searching capacity. We assessed 21 variables including gender, age, stage and admission period. We calculated 5-years CS and stratified 5-years CS according to disease- and host-related risks. Component-wise likelihood-based boosting and variables selected by boosting were investigated in a multivariable Cox model. Results: The OS probabilities at 5- and 10- years were 50% and 25%, respectively. The 5-year CS probabilities remained almost constant over the years a patient had already survived after initial diagnosis (~50%). According to baseline variables, conditional survival estimates showed no gender differences. The estimated 5-year survival probabilities varied substantially, from 25% for patients ages 70 or older to 65% for patients younger than 60 years. Similarly, patients with D&S stage I have an estimated 5-year survival probability of about 75% compared with 40% for patients with D&S stages II and III. Significant risk factors via Cox proportional hazard model were D&S stage II+III, age >70 years, hemoglobin <10g/dl, ß2-MG ≥5.5mg/dl, LDH ≥200U/l. Renal impairment, low albumin and unfavorable cytogenetics increased the risk, but failed to reach significance. Cytogenetics, response, response duration and other risk parameters post treatment are currently included in our assessment. Of note, over the study period, admission of patients <60 years decreased from 60% to 34%, but increased for those ≥70 years from 10% to 35%, respectively, illustrating that not only young and fit, but also elderly patients are increasingly treated within large referral and university centers and that patient cohorts and risks do not remain constant over time. Conclusions: Conditional survival has attracted attention in recent years either in an absolute or relative form where the latter is based on a comparison with an age-adjusted normal population being highly relevant from a public health perspective. In its absolute form, conditional survival constitutes the quantity of major interest in a clinical context. We defined conditional survival by using the fact that the patient is alive at the prediction time s as the conditioning event. Alternatively, one could determine conditional survival, given that the patient is alive and progression-free or alive, but has progression at time s (Zamboni et al. JCO 2010). Analysis of the above and additional variables from diagnosis to prediction time s may refine conditional survival towards an even more specifically determined prognosis; follow-up response and risk parameters most likely further refining these CS analyses. Figure 1. Figure 1. Disclosures Wäsch: MSD: Research Funding; Janssen-Cilag: Research Funding; Comprehensiv Cancer Center Freiburg: Research Funding; German Cancer Aid: Research Funding.

Download Full-text

Active Immunotherapy with FavId® (Id/KLH) Following Rituximab Induction: Long-Term Follow-Up of Response Rate Improvement (RRI) and Disease Progression in Follicular Lymphoma Patients (pts).

Blood ◽

10.1182/blood.v108.11.691.691 ◽

2006 ◽

Vol 108 (11) ◽

pp. 691-691 ◽

Cited By ~ 2

Author(s):

Omer N. Koc ◽

Charles Redfern ◽

Peter H. Wiernik ◽

Fred Rosenfelt ◽

Jane N. Winter ◽

...

Keyword(s):

Disease Progression ◽

Median Time ◽

Response Rate ◽

Published Data ◽

Late Response ◽

Gm Csf ◽

Best Response ◽

Long Term Follow Up

Abstract Background: Studies of Id/KLH immunotherapy in treatment naïve (TN) fNHL pts following first remission from chemotherapy have demonstrated a prolonged duration of remission. We expanded this approach in a PhII trial to include TN and relapsed/refractory (R/R) pts with stable disease (SD) or PR or CR/CRu following 4 wkly doses of rituximab. We report here long term follow up of RRI, defined as the % of pts who converted from SD to PR or PR to CR/CRu following initiation of Id/KLH treatment, and analysis of disease progression. Treatment: Pts received rituximab (375mg/m2 i.v. wkly x 4 during wk1–4) and those with stable or responsive disease received Id/KLH (1 mg s.q. mo x 6) starting on wk 12 along with GM-CSF (250 mcg, s.q.) on days 1–4. Pts continued to receive booster injections on a reduced schedule until disease progression. Radiological scans, performed every 3 mos, were reviewed centrally. Disease progression and response were assessed using modified Cheson criteria. This data analysis was performed 32 mo from end of enrollment. Results: 103 pts were enrolled and received rituximab; 89 pts had ≥SD and received Id/KLH + GM-CSF of whom, 54 were R/R, and 35 were TN. The overall response rate (ORR) was 47% (42/89) at mo 3. After the initiation of Id/KLH dosing, ORR improved to 63% (56/89). In RRI pts, median time to best response was 9.1 mos from start of rituximab treatment (5.2 – 29.6 mos). 12 of 39 PR pts (31%) converted to CR/Cru. 14 of 43 SD pts (33%) converted to PR. Pt Groups # of Pts % Prog Free Median TTP Est by K-M (mo) Pts w/RRI 26 69% 37.9 TN rituximab responders 23 70% Not Reached (NR) Rituximab responders (All) 42 60% NR Non Responders (All) 47 36% 14.9 All Pts 89 47% 18.2 TN Pts (All) 35 66% NR Relapsed Pts (All) 54 37% 16.8 Conclusion: RRI following FavId is seen in nearly one third of pts. The magnitude of this improvement, the number of conversions to CR/CRu and median time to best response (9 mo and as late as 29.6 mo) suggests this is likely to be a FavId effect rather than late response to rituximab. Responders and TN pts show more durable responses compared to previously published data for rituximab therapy. FavId may also confer a benefit for nonresponders and R/R pts relative to rituximab alone. To confirm benefit of FavId following rituximab induction, a placebo controlled PhIII study was initiated; it completed enrollment in Jan 06. RRI data from this study is expected to be available in Nov 06.

Download Full-text

Bortezomib, Melphalan, Prednisone and Thalidomide Followed by Maintenance with Bortezomib and Thalidomide (VMPT-VT) for Initial Treatment of Elderly Multiple Myeloma Patients: Updated Follow-up and Impact of Prognostic Factors

Blood ◽

10.1182/blood.v116.21.620.620 ◽

2010 ◽

Vol 116 (21) ◽

pp. 620-620 ◽

Cited By ~ 6

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Maide Cavalli ◽

Roberto Ria ◽

Massimo Offidani ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Weekly Infusion ◽

Risk Of Disease ◽

Grade 3

Abstract Abstract 620 Background. The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for elderly newly diagnosed multiple myeloma. This phase 3 study compared the 4 drug combination bortezomib-melphalan-prednisone-thalidomide followed by maintenance bortezomib-thalidomide (VMPT-VT) with VMP alone. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). The primary end point was progression-free survival (PFS). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were superior in the VMPT-VT group with a complete remission (CR) rate of 38% vs 24% (p=0.0008). After a median follow-up of 26.1 months, the 3-year PFS were 55% in patients receiving VMPT-VT and 38% in those receiving VMP (HR 0.65, 95% CI 0.49–0.85, P=0.002, Table). The 3-year time-to-next-therapy were 69% with VMPT-VT and 55% with VMP (HR 0.60, 95% CI 0.42–0.85, P=0.004). The 3-year overall survival was 86% with VMPT-VT and 84% with VMP (HR 0.88, 95% CI 0.53–1.45, P=0.62). The achievement of CR was a strong predictive factor of longer PFS in both groups (P=0.0001): in VMPT-VT arm, 3-year PFS was 66% in patients who obtained CR and 47% in those achieving PR; in VMP arm, it was 70% and 30%, respectively. The PFS benefit of VMPT-VT was seen consistently across different subgroups defined by creatinine clearance, LDH and bortezomib schedule; by contrast, in patients older than 75 years (HR 0.87; 95% CI 0.54–1.43, P=0.59) and in those at increased risk of disease progression, defined as presence of cytogenetic abnormalities [t(4;14) or t(14;16) or del17p] and ISS 3 (HR 1.35; 95% CI 0.45–4.06, P=0.60), VMPT-VT seemed not to add any significant PFS advantage to VMP. Grade 3–4 neutropenia (38% vs. 28%, p=0.02), cardiological events (10% vs. 5%, p=0.04) and thromboembolic events (5% vs. 2%, p=0.08) were more frequent among patients assigned to the VMPT-VT group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. In both groups, the once-weekly infusion of bortezomib significantly reduced the incidence of severe sensory peripheral neuropathy from 16% to 3% (p<0.0001). One hundred and forty-nine VMPT-VT patients were assessable for maintenance treatment. After a median duration of maintenance of 14.4 months, the PR rate was 90%, including 45% CR. The 1-year landmark analysis of PFS in patients completing the 9 induction cycles, showed a 2-year PFS of 63% in the VMPT-VT group and 40% in the VMP group, demonstrating that maintenance with VT reduced the risk of disease progression of 51% (HR 0.49, 95% CI 0.33–0.72, p=0.0003, Figure). This advantage was less evident in patients older than 75 years (HR 0.97, 95% CI 0.52–1.78, P=0.91) and in those with high-risk of disease progression, defined as presence of cytogenetic abnormalities and ISS 3 (HR 1.31, 95% CI 0.22–7.85, p=0.77). Continuous therapy with VT had favourable safety profile: 3% of patients experienced grade 3–4 hematological toxicity, 5% grade 3–4 peripheral neuropathy and 7% discontinued due to adverse events. Conclusion. In summary the current results indicate that: 1. VMPT-VT prolonged PFS with an unprecedented 3-year PFS of 55% in elderly patients; 2. once-weekly infusion of bortezomib improved safety without affecting outcome; 3. higher dose-intensity regimens seemed to be less effective in frail patients (≥ 75 years) and 4. maintenance therapy with VT further improved PFS with a good safety profile. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria. Patriarca:Celgene: Honoraria; Janssen Cilag: Honoraria; Roche: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Petrucci:Celgene: Honoraria; Janssen Cilag: Honoraria. Musto:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text