Background: clofarabine (CLO) is a nucleoside analogue with efficacy in acute myeloid and lymphoblastic leukemia (ALL). We evaluated whether CLO added to induction and consolidation would improve ...event free survival (EFS) in adult patients.
Methods: patients, aged 18-70 years, with newly diagnosed precursor B- or T-ALL were eligible and randomized for standard treatment or combined with CLO. Standard treatment for younger (18-40 years) patients consisted of a pediatric inspired schedule (HOVON70, Rijneveld et al. 2011) and older patients (41-70 years) were treated with a semi-intensive schedule (HOVON71, Daenen et al. 2012). Patients with Ph positive ALL received imatinib during treatment, but not in combination with CLO. Patients were stratified according to age and immunophenotype (B- vs T-ALL). CLO (5 days, 30 mg/m2) was administered during 2 courses, i.e. during prephase with prednisone and as a single drug during a second consolidation course. The CLO dose was established during a run-in phase and was approved by the DSMB. High risk disease was defined as high WBC count at diagnosis, no CR after induction or high risk cytogenetic/molecular abnormalities (Ph or BCR-ABL positivity, MLL aberrations, hypodiploidy and complex karyotype). Allogeneic stem cell transplantation (alloSCT) with an HLA identical sibling donor was offered as consolidation to all patients and in patients with high-risk ALL a sibling or alternative donor was used. Primary endpoint was EFS. Secondary endpoints included CR, MRD measured by RQ-PCR of rearranged Ig or TCR genes, disease free (DFS) and overall survival (OS), toxicities and treatment related mortality. This trial was supported by Sanofi Genzyme and registered at www.trialregister.nl as NTR2004.
Results: between December 2010 and November 2016, 340 patients were randomized. Here we report results of the first 120 younger and 120 older patients, i.e. 240 patients in total. No differences between study arms were observed with respect to pretreatment characteristics including age (median 41 year), risk group, Ph positivity, WHO-PS and immunophenotype. Respectively, 80% and 73% of patients ≤40 years completed protocol treatment according to arms A (control) and B (CLO); these percentages were 67% and 62% for patients >40 years. Estimated EFS was 49% and 46% at 5 years from randomization for arm A and B resp. (hazard ratio (HR): 1.05, 95% confidence interval (CI): 0.72-1.51, p=0.81; adjusted for age and phenotype). For patients ≤40 years, 5-year EFS was 58% vs 55% in arm A vs B, while in patients > 40 years EFS was 41% vs 29% in arm A vs B. CR rate was 87% and 88 % in arm A vs B and in both age groups. MRD was assessed at multiple time points during treatment and available for 117 (48%) patients, 58 and 58 in arm A and B resp. MRD response was defined by levels <10-4. 37/58 patients (64%) obtained MRD after consolidation 1 in arm A vs 49/59 (83%) in arm B (p=0.022). 49 (41%) of patients proceeded to alloSCT in arm A vs 54 (45%) in arm B (p=0.60). After a median follow up of 40 months (range: 1-72), 5-year OS was 59% in arm A vs 51% in arm B (HR = 1.17, 95% CI: 0.78-1.76, p=0.45). In patients who reached CR, 5-year DFS was 56% in arm A and 53% in arm B (HR = 1.08, 95% CI: 0.70-1.66, p=0.74), while 5-year relapse rates were 27% and 25% (HR = 1.03, 95% CI: 0.58-1.81, p=0.92), and 5-year non-relapse mortality was 17% vs 22 % (HR = 1.15, 95% CI: 0.59-2.25, p=0.69). No significant differences with respect to EFS, OS, and DFS emerged after evaluation with censoring of alloSCT recipients. Serious adverse events (SAEs) were slightly more often observed in CLO treated patients: 71% vs 82% in ≤40y (p=0.28) and 54% vs 65% in >40y (p=0.27). More infections grade 3-4 were observed in CLO treated patients: 44 vs 64% in arm A and B resp. (p=0.003).
Conclusions: while complete evaluation of all 340 randomized patients is still ongoing, analysis of the first 240 randomized patients with sufficient follow-up (med 40 months) shows that addition of CLO is feasible. Toxicities included a non-significant increase of SAEs and a significant increase of infections. So far, a non-significant lower number of patients receiving CLO fully completed protocol treatment. Despite a higher MRD response in the CLO arm EFS, DFS and OS were not improved so far. Longer follow-up and analysis of all patients is required to determine whether a better MRD response translates into better outcome.
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Rijneveld:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz pharmaceuticals: Research Funding. Petersen:Sanofi: Membership on an entity's Board of Directors or advisory committees. Selleslag:Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schipperus:Amgen: Research Funding.
Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this ...population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66-81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (
= 116), days 1-21. In the second cycle, patients received cytarabine 1000 mg/m
twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60-77%) vs 64% (55-73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (
= 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.
BACKGROUND
There is a high rate of toxicity-related discontinuation in elderly patients with NDMM, which in general is higher in patients ≥75 years. Therefore, we investigated the feasibility of a ...dose-adapted MPV scheme in patients ≥75 years and whether the International Myeloma Working Group frailty score (fit, unfit, and frail) predicts feasibility. Moreover, geriatric assessments, including functional assessments, were performed in order to design a model for more precise prediction of feasibility of treatment.
METHODS
Patients were treated with 9 cycles of MPV: Mel 6 mg/m2, day 1-4; Pred 30 mg/m2, day 1-4; and Bort 1.3 mg/m2 day 1,8,15 and 22 of a 35-day cycle. This first planned analysis on discontinuation rate was restricted to the first 100 eligible consecutive patients out of 240 planned patients. A preliminary analysis of grip strength and walking speed was performed, comparing tertiles.
RESULTS
Of the 96/100 evaluable patients, none were fit (because of age ≥75 years), 23/96 (24%) were unfit and 64/96 (67%) were frail (9/96 (9%) unknown). 28/64 (44%) frail patients were aged 75-80, and 8/64 (13%) patients were defined frail based on age >80 years only. Frail patients were found to have significantly less grip strength and lower walking speed as compared to unfit patients (see table 1), both for men and women. However, 19% (male) and 15% (female) of the patients with low grip strength were not frail, but unfit. For slow walking speed these percentages were 13% and 7% respectively, indicating these tools might be complementary to the IMWG frailty score in predicting outcome.
The median follow up was 16 months. The discontinuation rate of MPV in the total population was 49%; 30% in unfit and 55% (including 7% discontinuation of bortezomib only) in frail patients (p=0.055). In patients >80 years (by definition frail) discontinuation rate was higher (69% (including 11% bortezomib only)) than in patients aged 75-80 years (37%; p=0.003). Reasons for early discontinuation in unfit versus frail were: progressive disease 1/7 vs 4/31, toxicity 3/7 vs 10/31, death 0/7 vs 4/31, non-compliance 1/7 vs 8/31, other 2/7 vs 5/31. In 72% 6 cycles of MPV were found to be feasible, both in unfit (78%) and frail (73%) patients.
Response on protocol was ≥PR 69%, ≥VGPR 29% and ≥CR 7%, not significantly different in unfit versus frail patients. Median progression free survival (PFS) was 17 months: 22 for unfit and 17 months for frail patients (p=0.38). Overall survival (OS) at 18 months was 76%: 88% for unfit and 71% for frail (p=0.26) patients.
Conclusions
Treatment of elderly NDMM patients ≥75 years with 9 cycles of dose-adjusted MPV results in a high discontinuation rate of 49%: 30% in unfit versus 55% in frail patients, indicating the need for further treatment adjustment and more precise selection of patients. Concerning the first; 6 cycles were found to be feasible in the majority of both unfit and frail patients. Concerning the latter; a preliminary analysis of functional geriatric assessments showed significantly lower performance in frail compared to unfit patients. Moreover, the results of functional geriatric assessments were found to add to the IMWG frailty score, hopefully leading to a better prediction of the feasibility of treatment in elderly NDMM patients.
Functional assessments in unfit versus frail patients 1 p=0.18 2 p=0.012 3 p=0.0374 p=0.014
Additional cognitive and nutritional geriatric assessments and biomarkers (sarcopenia and senescence markers) were performed in all patients.
FISH analysis of isolated plasma cells will be available in the majority of patients.
This trial was registered at www.trialregister.nl (NTR 4244), EudraCT 2013-000320-33, and supported by the Dutch Cancer Society (project number VU 2013-6411 ) and by an unrestricted grant from Janssen-Cilag.
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Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Ypma:Advisory Board Sanofi (Plerixafor): Membership on an entity's Board of Directors or advisory committees. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. van de Donk:BMS: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.
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Purpose: This randomized phase II study (HOVON89) in patients with low/int-1 risk MDS refractory or unlikely to respond to erythropoietin and granulocyte-colony stimulating factor (EPO/G-CSF) ...assessed efficacy and safety of lenalidomide without (Arm A) or with EPO+/-G-CSF (Arm B) in case of no erythroid response after 4 cycles.
Patients and methods: In total 200 patients were randomly 1:1 assigned to either Arm A or Arm B. All patients were treated with lenalidomide (10 mg/day/day 1-21) for a minimum of 6 months in arm A and 12 months in arm B or until loss of response or disease progression. Patients in arm B without hematological improvement-erythroid (HI-E) after 4 cycles received EPO (30,000 IU/wk). In those patients who did not show HI-E after 6 months, EPO was increased to 60,000 IE/wk. G-CSF (3x 300-480 µg/wk) was added if no HI-E was reached at 8 month. The current pre-final evaluation was based on the first180 patients and included 85% non-del5q MDS and15% patients with isolated del5q. The median age was 71years (range 38-89). No differences were observed between both arms regarding sex (55% male), WHO PS, WHO diagnostic subgroup and IPSS, baseline Hb, WBC, platelets, endogenous erythropoietin level, pretreatment with EPO+/-G-CSF (67% of the patients were pretreated) and pre-study transfusions. Patients had received a median of 13 (range 0-72) units of RBC and 4 (range 0-13) within 8 weeks for prior study entry.
Results: Adverse events were consistent with the known safety profile of lenalidomide/EPO/G-CSF. HI-E according to IWG criteria was achieved in 38% and 41% of the patients for arm A and B, respectively (p = 0.46). HI-E was significantly lower in non-del5q versus del5q patients (33% vs 78%, respectively). Time-to-HI-E was 3.1 months (median; range 1.6-12.3) for both arms with a median duration of 10 months (range 1 - 76). The median PFS was 14.4 vs 15.4 months in arms A and B (p=0.43). OS was 51.1 and 37.7 months for arm A and B (p=0.09). At 2 years 17% of patients had progressed to AML (no differences between arms). The median FU of patients still alive is 31 months. PFS and OS was significantly longer in those who achieved HI-E, (median 13 vs 19 months, p=0.02 for PFS and median 31 vs 63 months for OS, p<0.001); non-responders vs responders). A Landmark analysis at 12 month confirms a significant prolonged OS in patients who achieved HI-E (28 and 51 months, p<0.002, non-responders vs responders). Endogenous erythropoietin level, pretreatment with EPO/G-CSF, and WHO subgroup did not predict for HI-E, PFS and OS. However, an IPSS of 0 was favorable in comparison to a score of 0.5-1.0 (p=0.02). To better predict response we are currently analyzing baseline flowcytometry and NGS data.
Conclusion: Lenalidomide yields sustained HI-E in 33% of patients with non-del5q low/int-1 risk MDS refractory or unlikely to respond on EPO/G-CSF. The addition of EPO/G-CSF did not improve HI-E. Achievement of HI-E significantly improves PFS and OS.
Ossenkoppele:J&J: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Karyopharm: Consultancy, Research Funding; Novartis: Research Funding.
Introduction
We previously reported the results of the phase III randomized HOVON-87/NMSG-18 study for Newly Diagnosed Multiple Myeloma patients not eligible for stem cell transplantation (nte-NDMM). ...The efficacy of melphalan, prednisolone and either thalidomide followed by thalidomide maintenance (MPT-T) versus lenalidomide followed by lenalidomide maintenance (MPR-R) was found to be comparable, being consistent across subgroups defined by age, cytogenetic risk and ISS 1. As frailty is known to affect clinical outcome, we investigated the impact of frailty on outcome.
Methods
Frailty was assessed by a modification of the IMWG frailty score based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living ((i)ADL). To assess the effect of frailty on progression free survival (PFS) and OS, the logrank test was used, while the chi-squared test was used to evaluate the association of frailty with discontinuation rate and toxicity.
Results
All 637 eligible patients from the HOVON-87/NMSG-18 trial were included in the analysis. Median age was 73 years; 66% of patients were ≤ 75 years, 24% were 76-80 years and 10% were > 80 years. A CCI of 0, 1, 2 and ≥3 was found in 61, 20, 7 and 4% of patients respectively (8% unknown). The most common comorbidities were diabetes mellitus without end organ complications (12%) and myocardial infarction (6%). A WHO performance of 0, 1 and ≥ 2 was observed in 35, 47 and 16% respectively (3% unknown).
Univariate analyses showed that older age (>80 years: HR 1.59 95% CI 1.12-2.25), a higher CCI (CCI ≥2: HR 1.41 95% CI 1.01-1.95); and a poor WHO performance (WHO ≥2: HR 2.05 1.49-2.82) were associated with an inferior OS. HR's were 1.07 95% CI 0.82-1.40 and 1.27 95% CI 0.98-1.65 for age 76-80 years and WHO performance respectively. For age and the CCI the IMWG frailty score classification was used. For the WHO, scores were assigned based on the HR: WHO 0; 0 points, WHO 1; 1 point and WHO ≥2; 2 points. Fit patients were defined as a proxy frailty score of 0, unfit as a score of 1 and frail as a score of ≥2, comparable to the IMWG frailty score.
Using this modified IMWG frailty score, 135 patients were fit (21%), 199 were unfit (31%) and 259 were frail (41%) (7% unknown). The median OS was found to be significantly different in fit versus unfit versus frail patients; 58, 55 and 46 months respectively (p=0.004). In contrast no significant difference in median PFS was found; 26, 20 and 21 months respectively (p=0.30).
The inferior OS for the frail might be partly explained by higher discontinuation rate of induction therapy; 50%, versus 43% in unfit, and 34% in fit patients (p=0.011), being mainly due to excessive toxicity (25, 23 and 16% respectively). The cumulative incidence of treatment discontinuation on protocol (induction plus maintenance), corrected for death and progressive disease which were considered as competing risks, is depicted in figure 1B. Discontinuation rate at 2 years for fit, unfit, and frail patients were 48%, 48%, and 59% respectively (p=0.06). There were significantly more grade ≥3 adverse events on protocol in frail and unfit patients (both 86%) as compared to fit patients (77%, p=0.039). Especially more grade ≥3 infections were found in frail (28% versus 18% in unfit and 13% in fit). In contrast, frailty was not associated with hematological toxicity.
Conclusion
We here present a modified frailty score, using the WHO performance instead of the (i)ADL, combined with age and the CCI, that enables the identification of frail MM patients with an inferior OS, a higher discontinuation rate and a higher rate of grade ≥ 3 toxicity. This non-laborious modified frailty score can be easily implemented in clinical trials and allows to compare the outcome of frail patients in nte-NDMM trials, which will hopefully result in frailty-adapted therapy in clinical daily practice.
Reference:
1. Zweegman S, Holt vd B, Mellqvist U, et al. Blood 2016;127(9):1109-16
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Mellqvist:Celgene: Honoraria; janssen: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Sandoz: Other: participation advisory board; Amgen: Honoraria, Other: participation advisory board. Abildgaard:Takeda: Research Funding. Plesner:Janssen: Research Funding; Janssen, Takeda: Consultancy; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees. Van De Donk:Janssen, Celgene, Bristol-Myers Squibb, Amgen: Research Funding. Sonneveld:Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy. Waage:Celgene, Takeda: Honoraria. Zweegman:Celgene: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Takeda: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation.
This multicenter phase 2 trial investigated safety and efficacy of a new immunochemotherapeutic regimen combining rituximab (R) and fludarabine (F) in patients with fludarabine- and ...anthracycline-naive chronic lymphocytic leukemia (CLL). The rationale for using R + F includes single-agent efficacy of both drugs, in vitro synergism of R and F, and no apparent overlapping toxicity. Of 31 eligible patients with B-CLL enrolled, 20 were previously untreated and 11 relapsed. Treatment consisted of fludarabine administered at standard doses (25 mg/m2/d; days 1-5, 29-33, 57-61, and 85-89) and rituximab (375 mg/m2/d) given on days 57, 85, 113, and 151. Side effects such as fever, chills, and exanthema were generally mild (National Cancer Institute Common Toxicity Criteria NCI-CTC grade 1/2 in 48% and grade 3 and/or 4 in 3% of patients). Fever and chills were mainly associated with the first rituximab infusion. Hematologic toxicity included neutropenia (grade 1 and/or 2 in 26%, grade 3 and/or 4 in 42%) and thrombocytopenia (grade 1 and/or 2 in 19%, grade 3 and/or 4 in 9%). One patient died of cerebral bleeding during prolonged thrombocytopenia after the second cycle of fludarabine. There were a total of 32 infections in 16 patients, none of which was fatal. The overall response rate (complete remission CR and partial remission PR) was 87% (27 of 31 evaluable patients). In 20 previously untreated patients, 17 (85%) responded. Ten of 31 patients achieved CR (5 of 20 untreated; 5 of 11 pretreated; 9 of 21 Binet stage B, 1 of 10 Binet stage C). The median duration of response was 75 weeks. We conclude that the combination of rituximab and fludarabine is feasible and effective in patients with B-CLL.
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INTRODUCTION Daratumumab is an anti-CD38 monoclonal antibody (mAb) with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC ...(complement-dependent cytotoxicity). In current clinical phase I/II trials, daratumumab induced anti-MM activity; however, the depth of the response varied between patients. Up till now it is unknown what determines the intrinsic sensitivity of MM cells towards daratumumab-mediated ADCC and CDC. We examined potential determinants of daratumumab sensitivity including CD38 levels, the frequency of effector cells, and expression levels of the complement inhibitory proteins, CD46, CD55, and CD59, which interfere with the different steps of complement activation.
RESULTS In bone marrow samples from MM patients, we observed a significant correlation between CD38 expression and daratumumab-mediated ADCC (127 patients; R = 0.428; P < 0.0001) as well as CDC (56 patients; R = 0.338; P = 0.011). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38, revealed that the level of CD38 expression correlates with the extent of daratumumab-mediated ADCC and CDC. Other determinants of daratumumab susceptibility include the effector:target ratio for ADCC, and levels of the complement-inhibitory proteins CD55 and CD59 for CDC. Our data suggest that upregulation of CD38 expression may improve the anti-MM activity of daratumumab. Since, interaction of all-trans retinoic acid (ATRA) with nuclear retinoic acid receptors results in altered expression of target genes including induction of CD38 expression, we evaluated the combination of ATRA and daratumumab. As little as 10 nM ATRA was sufficient to induce a 1.9 – 4.4-fold increase in CD38 expression on the MM cell lines RPMI8226, UM9, and XG1, which resulted in a significant improvement of daratumumab-mediated ADCC and CDC. Importantly, 10 nM ATRA alone resulted in no or only a minimal increase in MM cell death. In addition, ATRA induced a 1.0 – 26.5 (median 1.7) fold increase in CD38 expression on primary MM cells from 26 patients. Also in these primary MM cells, pretreatment with ATRA resulted in a significant increase in their susceptibility to daratumumab-mediated CDC in 13 out of 16 patients as well as ADCC in 8 out of 11 patients. ATRA also enhanced the efficacy of daratumumab in MM cells which are completely resistant to daratumumab-mediated CDC and/or ADCC. Pooled results of these patients show that ATRA improved CDC mediated by 10 µg/mL daratumumab from 16.1 % to 43.9 % (P < 0.0001), and ADCC from 25.1 % to 39.5 % (P = 0.0315). Importantly, expression levels of CD55 and CD59 on MM cells were also significantly reduced by ATRA, which may explain that ATRA improves CDC to a higher extent than ADCC.
CONCLUSION Our results provide evidence that CD38 expression levels may predict response to daratumumab. Furthermore, we show that ATRA increases CD38 expression on MM cells, resulting in enhanced daratumumab-mediated lysis of MM cells. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.
Lokhorst:Celgene: Research Funding; J&J: Research Funding; Genmab: Research Funding. Martens:J&J: Research Funding. Doshi:Janssen R&D: Employment. Mutis:Genmab BV: Research Funding; J&J: Research Funding; Celgene: Research Funding. Sasser:Janssen R&D: Employment. van de Donk:Genmab BV: Research Funding; J&J: Research Funding; Celgene: Research Funding.
Abstract 1853
Bortezomib (1.3 mg/m2) combined with Lenalidomide (10–25 mg) and Dexamethasone (VRD) is effective in newly diagnosed and relapsed multiple myeloma (MM). Reported data on the effect of ...these drugs in relapse/refractory MM are available from the APEX and MM-009/MM-010 trials, respectively. These trials, however, were performed in patients with 2–8 prior regimens.
This investigator sponsored two-step phase 2 HOVON trial was designed to evaluate escalated dosages of Bortezomib (B) given once weekly and daily Lenalidomide (L) combined with weekly Dexamethasone (D) (eVRD) followed by Lenalidomide maintenance in an homogenous group of patients with symptomatic MM in first relapse. The goal was to explore the maximum tolerated dose of this combination in order to achieve a durable second remission.
Dose levels were B 1.3 mg/m2, L 10 mg, (level 1); B 1.6 mg/m2, L 10 mg (level 2); B 1.6 mg/m2, L 15 mg (level 3); B 1.6 mg/m2, L 20 mg (level 4). D dose was 20 mg days 1–2, 8–9, 15–16 in all dose levels. Inclusion criteria were symptomatic MM ISS stage 1–3, aged 18–80 in first relapse after initial treatment. The primary endpoint was response (complete response (CR) according to IMWG criteria, very good partial response (VGPR), partial response (PR), together overall response (ORR)) with Progression-free Survival (PFS), overall survival (OS) and toxicity as secondary endpoints.
Eighty-one patients were included, i.e. 15 patients in dose levels 1, 2 and 3, followed by 66 in the phase 2 part. This report is based on 12 patients in the dose escalation phase and the first 42 patients in the phase 2 part. Median age was 67 yrs, with ISS stages 1 (56%), 2 (40%) and 3 (5%). 37/54 patients had received HDM followed by stem cell transplant as part of first-line treatment. The MTD was reached at dose level 3 when the maximum of 3 SAEs in 5 patients was observed. After establishment of the MTD, the phase 2 part of the trial was performed with B 1.6 mg/m2 once weekly for 3 weeks, L 20 mg days 1–21 and D 20 mg days 1–2, 8–9, 15–16, for 8 cycles of 28 days followed by L maintenance 10 mg days 1–21 of a 28 days cycle. The median number of cycles was 6 in the dose-escalation phase and 7 cycles in phase 2. 7/12 (58%) patients in the dose-escalation phase and 23/42 (55%) patients in phase 2 started lenalidomide maintenance. Reasons for premature discontinuation of the protocol treatment were toxicity (14%), progression (24%), no response (5%) or other (14%). Polyneuropathy grade 3–4 occurred in 19% with a median time to maximum PNP of 123 days. Hematological toxicity grade 3 and 4 was observed in 29 % of patients In the phase 2 part including 42 patients the ORR was 92 %, ≥VGPR 64% and CR/nCR 30%. Median time to response was 1.1 cycles. At a median follow-up of 13.6 months PFS at 18 months was 52% and OS 76%. Among predetermined risk factors ISS stage, prior HDM/ASCT and achieved response on protocol, depth of response was the only significant factor which was associated with PFS (p<0.001) and OS (p<0.001), Eight patients died from progressive MM (n=4) or other causes (n=4). One second primary malignancy was observed in dose level 3.
Escalated VRD followed by Lenalidomide maintenance is effective and feasible in patients with first relapse MM. We will present an updated follow-up at ASH
This trial was registered as Eudract nr 2007–002533–37. Unrestricted grants and study drug were provided by Janssen and Celgene.
Sonneveld:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding.
Flow cytometric analysis is a recommended tool in the diagnosis of MDS. It is used to underline the diagnosis based on dysplastic features by cytomorphology and typical cytogenetic abnormalities ...(gold standard). Current MDS flow cytometry (MDS-FC) scoring systems that evaluate the maturing myelo-/monocytic lineage reach a median sensitivity and specificity of approximately 71% and 93%. Since anemia is the most common feature in MDS, it was hypothesized that addition of in depth analysis of the erythroid lineage could increase the sensitivity of MDS-FC. We analyzed 176 bone marrow aspirates by MDS-FC, including 110 patients with MDS (low/int-1 risk) within a prospective multicenter clinical trial and 66 pathological controls (i.e. iron deficiency, iron incorporation disorders, vitamin B12 deficiency, cytopenia due to medication or chronic disease, aplastic anemia, and PNH). For erythroid lineage analysis, markers recommended by the ELNet iMDS-flow group including i.e. expression level of CD71 and CD36 and percentage of erythroid progenitors cells (CD117 positive or CD105 positive cells) were explored. Data from erythroid analysis were added to a previously described MDS-FC scoring system (Van de Loosdrecht JNCCN 2013). This scoring system combines the diagnostic MDS-FC score (Della Porta Haematologica 2012), analysis of myeloid progenitor cells, and of the granulocytic and monocytic cell compartment (Wells Blood 2003). At initial assessment the MDS-FC method categorized 75/110 MDS patients as ‘compatible with MDS’ (true positive), 23/110 as ‘minor MDS related aberrancies’, and 12/110 patients as ‘not compatible with MDS’ (false negative). Within the pathological control group: 45/66 were ‘not compatible with MDS’ (true negative), 20/66 showed ‘minor MDS related aberrancies’, and 1/66 ‘compatible with MDS’ (false positive). Calculated sensitivity and specificity of MDS-FC without taken into account erythroid analysis were 68% and 98%, respectively, in line with previous studies. Results of the erythroid FC analysis showed 82/110 MDS patients with clear dyserythropoiesis compared to 16/66 of the pathological controls. A strong correlation between presence of dyserythropoiesis by MDS-FC and the diagnosis of MDS as assessed by morphology was found (Pearson’s R=0.71; p<0.001). Results derived of the erythroid analysis were added to the MDS-FC scoring system. This resulted in: 94/110 MDS patients ‘compatible with MDS’, 13/110 patients with ‘minor MDS related aberrancies’, and 3/110 patients ‘not compatible with MDS’. Compared to 40/66 pathological controls that were ‘not compatible with MDS’, 23/66 that showed ‘minor MDS related aberrancies’, and 3/66 that were ‘compatible with MDS’. Although dyserythropoiesis by CM can be present in pathological controls, dyserythropoiesis by FC remained highly specific for MDS. Calculated sensitivity increased to 85%, with only a minor decline in specificity (95%). In conclusion, addition of the erythroid lineage analysis to a diagnostic MDS-FC score system led to an increased sensitivity, as validated within this prospective clinical trial. These data indicate that if translating to routine clinical practice, the erythroid integrated MDS-FC approach is highly instrumental in refinement of MDS diagnosis.
De Greef:Celgene: Consultancy. Van de Loosdrecht:celgene: Honoraria, Research Funding; alexion: Research Funding.
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