Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome.

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65-80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1-24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1-6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69-91%) vs. 59% (45-72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl ).

Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.

Guideline for diagnosis and treatment of Waldenström's macroglobulinaemia.

On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenström's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012.

Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study.

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T(0)). The median age at diagnosis was 58 years, and time from diagnosis to T(0) was 3.3 years. Following T(0), 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T(0) in 94 patients (44%) including ≥ partial response in 69 (32%). The median overall survival and event-free survival from T(0) were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

[Neoadjuvant chemotherapy of breast carcinomas: what post-therapeutic (preoperative) information is provided by quantitative dynamic MRI?]. / Neoadjuvante Chemotherapie des Mammakarzinoms : Welche posttherapeutischen (präoperativen) Informationen liefert die quantitative dynamische MRT?

PURPOSE: The aim of this study was to evaluate whether quantitative changes in contrast enhancement (CE) after neoadjuvant chemotherapy (NC) are associated with histological signs of tumor regression and whether quantitative dynamic MRI (dMRI) is capable of accurately assessing preoperative tumor size compared to mammography (MG) and ultrasound (US). METHODS: Thirty-one patients with breast cancer underwent MRI before and after NC. Dynamic CE was measured using a turbo-FLASH sequence and quantified by a two-compartment model, where two parameters, k(ep) (distribution constant rate) and A (amplitude), were calculated and color mapped. RESULTS: When tumors had signs of histological regression in the operative specimen (n=17) decrease of the parameters A and k(ep) was significantly more marked compared to tumors without regression (n=12). The correlation between tumor size measured by dMRI and histopathology was 0.81 when areas of unspecific CE were included; when they were not included the correlation was 0.66 and tumor size was systematically underestimated. In 26 patients dMRI was retrospectively compared with MG (r=0.51; dMRI, r=0.80) and in 22 patients with US (r=0.60; dMRI, r=0.75). CONCLUSION: Changes in dynamic CE are associated with histological tumor regression. Quantitative dMRI enables a valid assessment of tumor residue and is superior to MG and US. Remaining unspecific CE within the original tumor site should be considered as potentially malignant.

Accuracy of tumor size measurement in breast cancer using MRI is influenced by histological regression induced by neoadjuvant chemotherapy.

The aim of this study was to evaluate whether regressive changes after neoadjuvant chemotherapy for breast cancer affect the accuracy of preoperative MRI measurements of tumor size. Thirty-one patients with breast cancer underwent MRI before and after neoadjuvant treatment. Besides pre- and post-contrast T1-weighted MRI, dynamic MRI with high temporal resolution (turbo-FLASH) was performed. Contrast enhancement in dynamic MRI was quantified using a pharmacokinetic two-compartment model, where two parameters, amplitude and k(ep), were calculated and color coded on transversal parameter maps. Considering the conventional MR images, tumor diameters were measured on the color maps and compared with histological tumor size. Histological regression was scored on a five-point scale regarding cytopathic effects, reactive changes, and tumor cell reduction. The correlation between tumor sizes measured by MRI and histopathology was 0.83 ( p<0.0007) in 12 tumors without regressive changes (score 0), and 0.48 ( p<0.051) in 17 tumors with regressive changes scored 1 or 2, without any tendency for systematic over- or underestimation. In two cases without residual tumor (score 4), MRI likewise showed no signs of persistent tumor. The decrease of the contrast enhancement parameters was significantly more marked in tumors with signs of histological regression than in those without. Whenever MRI is used to judge the response of breast cancer to chemotherapy, the reader must be aware that therapy-induced changes may cause significant over- or underestimation of tumor size. We saw a high precision only when there was either no response - according to histological criteria - or when the tumor had regressed completely.

Evaluation of neoadjuvant chemotherapeutic response of breast cancer using dynamic MRI with high temporal resolution.

The aim of this study was to evaluate changes in both size and contrast enhancement of breast tumors during neoadjuvant chemotherapy, using dynamic MRI with high temporal resolution. Patients with advanced breast cancer (n=21) underwent a 1.5-T MRI scan prior to and following neoadjuvant chemotherapy with four cycles. Dynamic contrast enhancement was measured using a fast turbo-FLASH sequence and quantified using a two-compartment model with the parameters k(ep) and amplitude. Image analysis was done on images overlayed with a color map of parameters. The correlation between tumor diameter measured by histopathology and MRI was 0.7 (p<0.003). A reduction of tumor size after chemotherapy of more than 25% was associated with a decrease of both analyzed contrast enhancement parameters (k(ep): p<0.002; amplitude: p<0.006), where k(ep) began to drop already after the first cycle of chemotherapy (p<0.008). A clear reduction of tumor size was only noted after the third cycle (p<0.008). In patients without tumor regression there was also a trend towards an early reduction of contrast enhancement. We assume that MRI with high temporal resolution and color mapping is a novel tool to assess therapeutic effects of neoadjuvant chemotherapy in breast tumors, which deserves further prospective evaluation.