Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase ...(BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a “snapshot” of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.
•In a real-life CLL cohort still on ibrutinib after 3 years, 57% of patients with residual clonal lymphocytosis had a BTK mutation.•The presence of a BTK mutation in patients still on ibrutinib conferred a greater likelihood of subsequent CLL progression.
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Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with ...standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.
Summary Background In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of ...thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival. Methods Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126). The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00367185. Findings After a median follow-up of 51·5 months (IQR 34·4–63·2), median overall survival times were 33·2 months (13·8–54·8) for MP, 51·6 months (26·6–not reached) for MPT, and 38·3 months (13·0–61·6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0·59, 95% CI 0·46–0·81, p=0·0006) or MEL100 regimen (0·69, 0·49–0·96, p=0·027). No difference was seen for MEL100 versus MP (0·86, 0·65–1·15, p=0·32). Interpretation The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should, at present, be the reference treatment for previously untreated elderly patients with multiple myeloma.
We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and ...acute kidney injury (AKI) without need for dialysis.
After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group).
Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41
47 responders in the BD and C-BD groups, respectively; relative risk RR, 0.87;
= .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76;
= .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group
10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died.
This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.
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INTRODUCTION: Erythropoiesis stimulating agents (ESA) are generally the first line of treatment of anemia in lower risk myelodysplastic syndrome (MDS) patients (pts) with a recent approval of ...epoetin alfa in this indication in EU. Predictive factors of response to ESA (E Hellström, BJH 2003, S Park et al, Blood 2008, V Santini et al, Blood 2013; O Kosmider et al., Haematologica 2016) include low RBC transfusion requirement, low serum EPO level, serum ferritin (SF) level<300ng/ml, low IPSS-R, and ≤2 somatic mutations. In a clinical trial using a biosimilar (epoetin zeta) in lower risk MDS pts, we investigated new biomarkers using flow cytometry (Ogata and Red Scores) (Mathis et al, Leukemia 2013), somatic mutations, GDF-15 and hepcidin levels.
METHODS: Main inclusion criteria for this multicenter prospective trial involving 16 French centers from 2013 to 2017 were: (1) IPSS low or int-1 MDS (2) ESA naive, (3) with Hb level< 10g/dL, transfusion dependent (TD) or not (4) without unstable cardiovascular disease, renal failure, folates, vitamin B12 or iron deficiency or active inflammatory status. Pts received epoetin zeta 40000 IU/week for at least 12 weeks and erythroid response (HI-E, IWG 2006 criteria) was assessed at W12. sEPO level, iron homeostasis markers, Ogata and Red Score (RS), GDF15, hepcidin, and molecular analysis by NGS on a 39-gene panel were determined at baseline (T0), and Ogata and RS were reassessed at W12.
RESULTS: 70 pts were included. Median age was 78 years (range 57-93), M/F: 31/39. At inclusion, WHO classification was 22 RCMD, 19 RCUD, 14 RARS, 4 RAEB, 6 CMML, 2 del 5q-, 3 unclassifiable, IPSS was 43 low (61.4%), 27 int-1 (38.5%), and R-IPSS was 13 very low (18.5%), 47 low (67%), 9 int (13%) and high (0.7%). Twenty (28.5%) pts were TD (median of 2 RBC/ 8weeks). ECOG was ≥1 in 30 pts.
Median Hb level was 9.5g/dL (IQR 8.9-10), Transferrin Saturation (TS) 39% (IQR 28-56), SF 411 ng/ml (IQR 258-831), sEPO level 49 U/L (IQR 25-122). Median Ogata score was 1 (IQR 1-2) at T0 and 2 (IQR 1-2) at W12. Median Red score (RS) was 7 (IQR 5-7) at T0 (with 90% of pts having RS ≥3), and 5 (IQR 4.75-7) at W12.
Median GDF15 level was 1971 pg/ml (IQR 1236-2860). GDF15 was lower in IPSS low vs int-1 pts, and correlated with TS (p<0.003). Hepcidin level was 27 ng/ml (IQR 14-42; normal 1.3-26.4). Median hepcidin/ferritin ratio (HFR) was 5.5 (IQR 1.9-11.85). HFR was inversely correlated with MCV, serum iron, TS, GDF15, and RS at T0 and at W12, and with the number of mutations.
Before treatment, NGS was performed in 68 pts. Most frequent mutations involved SF3B1 (n=26), TET2 (n=18), ASXL1 (n=14), SRSF2 (n=9), DNMT3A (n=9), U2AF1 (n=7), IDH2 (n=6), and EZH2 (n=6). No, 1, 2, 3, 4 or 5 mutations were detected in 12, 12, 26, 10, 7 and 1 pts respectively, and 26% of pts had >2 mutations.
The erythroid response (HI-E) rate was 47.6%. Median duration of response was 13 months. Three pts progressed to AML. Twelve pts had died. Median OS was 41 mo.
Responders had significantly lower baseline RS (median 5 in responders vs 7 in non-responders, p=0.01), higher HFR (median 9 vs 4.8, p=0.04), lower IPSS (p=0.01). GDF15 tended to be lower in responders (1822 pg/mL) vs non-responders (2180 pg/mL; p=0.47). Age, sex, ECOG, blood cell count (ANC, platelets, Hemoglobin), number and type of mutations, IPSS-R, SF, sEPO level, T0 and W12 Ogata score, previous RBC transfusions, decrease of RS and of Ogata score between T0 and W12 were not significantly associated with response. In multivariate analysis, only RS≥5 at T0 was significantly associated with worse HI-E (p= 0.007, OR 19, 95% IC: 2.1-476). HI-E was 39% in pts with RS≥5 vs 75% in pts with RS<5.
CONCLUSION: Erythroid response (HI-E) to epoetin zeta was 48% in lower risk MDS and was correlated with higher baseline hepcidin/ferritin ratio and lower Red score at T0. In multivariate analysis, only Red Score≥5 was associated with worse HI-E, in this population with very low median sEPO level.
Maloisel:Pfizer/Hospira: Research Funding. Drenou:Alexion: Consultancy, Honoraria. Fenaux:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Laribi:MUNDIPHARMA: Research Funding; NOVARTIS: Honoraria, Research Funding; ROCHE: Research Funding; TEVA: Research Funding; HOSPIRA: Research Funding; AMGEN: Honoraria; TAKEDA: Honoraria, Research Funding. Pegourie:Takeda, Novartis, Janssen, BMS: Consultancy. Wagner Ballon:Alexion: Consultancy, Honoraria. Park:Celgene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira/Pfizer: Research Funding.
Micro-Abstract Thalidomide monotherapy has demonstrated consistent results in the treatment of advanced multiple myeloma. We report a 9-year follow-up of a French multicenter nonrandomized phase II ...study that evaluated the effect of oral thalidomide in 120 patients with advanced multiple myeloma. Independent predictors of survival were response to last therapy, performance status, serum β2 -microglobulin level, platelet count, and response at day 60 of treatment.
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