CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia

CD 49d is a surface integrin that is expressed on chronic lymphocytic leukaemia (CLL ) cells, and strongly correlates with more aggressive disease. Given its association with cell‐cell adhesion and leucocyte trafficking, we hypothesized that patients with high CD 49d expression would experience a clinical course dominated by lymphadenopathy. CD 49d expression was measured by flow cytometry and considered positive if expressed by ≥30% of CLL cells. The study included 797 newly diagnosed CLL /small lymphocytic leukaemia patients; 279 (35%) were CD 49d positive. CD 49d‐positive patients were more likely to present with lymphadenopathy (P  <  0·001); a finding that persisted after adjusting for fluorescence in situ hybridisation (FISH ) and IGHV mutation status [odds ratio (OR ) 2·51; 95% confidence interval (CI ) 1·64–3·83; P  <  0·001]. Among CLL Rai 0 patients, CD 49d positivity was associated with shorter time to development of lymphadenopathy (3·2 years vs not reached, P  <  0·01). This association was maintained after adjusting for either FISH [hazard ratio (HR ) 2·18; 95% CI 1·25–3·81; P  =  0·006) or IGHV status (HR 2·02; 95% CI 1·11–3·69; P  =  0·02) individually, but was attenuated when adjusting by both (HR 1·72; 95% CI 0·88–3·38; P  =  0·11).These data demonstrate that CD 49d‐positive CLL patients experience a disease course dominated by lymphadenopathy. These findings could have implications for therapy selection and disease monitoring.     

Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases

We performed an external and multicentric validation of the nomogram and prognostic index (PI) proposed by the MD Anderson Cancer Center to prognostically stratify chronic lymphocytic leukaemia (CLL) patients in 1502 CLL cases. All six parameters involved in the nomogram and PI (age, sex, absolute lymphocyte count, number of lymph node groups, Rai stage and β2‐microglobulin) were independently associated with survival. The nomogram was accurate in predicting survival (c‐index = 0·82). According to the PI, 38·7% of patients were at low‐risk, 58·3% at intermediate‐risk and 3% at high‐risk. The estimated median survival times were: not reached for low‐risk, 13·4 years for intermediate‐risk and 3·4 years for high‐risk. The estimated median and 5‐year survival by PI were similar to those originally reported. The PI remained a predictor of survival when analysis was limited to 847 Rai stage 0 (P < 0·0001) and 151 clinical monoclonal B‐cell lymphocytosis (cMBL) cases (P = 0·033). Finally, the PI allowed prediction of time to therapy in all patients (P < 0·0001), in Rai 0 (P < 0·0001) and in cMBL cases (P = 0·044). Our results confirm the ability of the PI to predict prognosis, even in early stage disease cases. The study also extended the utility of the PI to cMBL cases.     

Diffuse large B‐cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients

Nearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B‐cell lymphoma [Richter syndrome (RS)] is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL between January 2000 and July 2011. Individuals who developed biopsy‐proven RS during follow‐up were identified. After a median follow‐up of 4 years, 37/1641 (2·3%) CLL patients developed RS. The rate of RS was approximately 0·5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (P < 0·001), high‐risk genetic abnormalitites on fluorescence in situ hybridization (P < 0·0001), unmutated IGHV (P = 0·003), and expression of ZAP70 (P = 0·02) and CD38 (P = 0·001). The rate of RS doubled in patients after treatment for CLL (1%/year). Stereotyped B‐cell receptors (odds‐ratio = 4·2; P = 0·01) but not IGHV4‐39 family usage was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS three‐fold (odds‐ratio = 3·26, P = 0·0003). Median survival after RS diagnosis was 2·1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0·5 years, 2·1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.     

Centre characteristics and procedure‐related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT)

The best approach for allogeneic haematopoietic stem cell transplantations (alloHCT) in patients with chronic lymphocytic leukaemia (CLL) is unknown. We therefore analysed the impact of procedure‐ and centre‐related factors on 5‐year event‐free survival (EFS) in a large retrospective study. Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five‐year EFS of the whole cohort was 37% (95% confidence interval [CI], 34–42%). Larger numbers of CLL alloHCTs (hazard ratio [HR] 0·96, P = 0·002), certification of quality management (HR 0·7, P = 0·045) and a higher gross national income per capita (HR 0·4, P = 0·04) improved EFS. In vivo T‐cell depletion (TCD) with alemtuzumab compared to no TCD (HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient (HR 1·4, P = 0·02) had a negative impact on EFS, but not non‐myeloablative versus more intensive conditioning. After correcting for patient‐, procedure‐ and centre‐characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non‐myeloablative conditioning appears to be the preferable approach for patients with CLL.     

Management of central nervous system involvement in chronic lymphocytic leukaemia: a retrospective cohort of 30 patients

Central nervous system involvement (CNS i) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL ). Establishing cause and effect between the CLL and the neurological symptoms remains challenging. We have analysed a retrospective cohort of 30 CLL patients with CNS i, documented by lymphocytic infiltration either by flow cytometry of the cerebrospinal fluid (CSF ; n  = 29) or CNS biopsy (n  = 1). Neurological symptoms were heterogeneous. At the time of CNS i, less than half of the patients had a progressive CLL and 20 had never been treated for CLL . Initial treatment with fludarabine‐based immuno‐chemotherapy, with or without intra‐CSF therapy, led to durable response in eight out of nine untreated patients. In contrast, 50% patients receiving various prior treatments needed additional therapy within a median of 4 months (1–16). Ibrutinib led to complete response in 4/4 heavily pre‐treated patients. From CNS i, 5‐year overall survival was 72% and 48% for treatment‐naïve and previously treated patients respectively (P  = 0·06); 5‐year progression‐free survival (PFS ) was 43% and 0% (P  = 0·125). 17p deletion was significantly associated with poor PFS (P  = 0·006). CNS i may be the only sign of progression of CLL and should be considered an initiation criterion of systemic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNS i itself.     

Minimal residual disease assessed by multi‐parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia

The prognostic value of minimal residual disease (MRD) assessed by multi‐parameter flow cytometry (MFC) was investigated among 340 adult patients with B‐cell acute lymphoblastic leukaemia (B‐ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15–84). Median white blood cell count (WBC) was 9·35 × 10⁹/l (range, 0·4–658·1 ×1 0⁹/l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15‐marker, 4‐colour panel and subsequently a 6‐colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease‐free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P < 0·0001, respectively) and OS (P = 0·004 and P < 0·0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0·05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL.     

Combined somatic mutation and copy number analysis in the survival of familial CLL

Recurrent large‐scale somatic copy number alterations (SCNAs), and somatic point mutations can be analysed to stratify patients with chronic lymphocytic leukaemia (CLL) into distinct prognostic groups. To investigate the relationship between SCNAs and somatic mutations, we performed whole‐exome sequencing and single nucleotide polymorphism microarray analyses on 98 CLL patients from 40 families with a high burden of CLL. Overall, 69 somatic mutations in 29 CLL driver genes were detected among 45 subjects (46%), with the most frequently mutated genes being TP53 (8·2%), NOTCH1 (8·2%) and ATM (5·1%). Additionally, 142 SCNAs from 54 subjects (57%) were detected, including losses of chromosome 13q14 (28·9%), 11q (5·6%), 17p (2·1%), and gain of chromosome 12 (4·2%). We found that patients having both an adverse point mutation in a CLL driver gene and an unfavourable SCNA tended to have poorer survival (Hazard ratio [HR] = 3·17, 95% confidence interval [CI] = 0·97–10·35; P = 0·056) than patients having either a point mutation (HR = 1·34, 95%CI = 0·66–2·71; P = 0·42) or SCNAs (HR = 2·65, 95%CI = 0·77–9·13; P = 0·12). TP53 mutation carriers were associated with the poorest overall survival (HR = 4·39, 95%CI = 1·28–15·04; P = 0·018). Our study suggests that combining SCNA and mutational data could contribute to predicting outcome in familial CLL.     

The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial

Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia (CLL) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re‐examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5–9%, 60 (12%) had 10–14% and 11 (2%) had ≥15% prolymphocytes. We show that a higher proportion of prolymphocytes (≥10%) was independently associated with NOTCH1 mutations (P = 0·006), absence of 13q deletion (P = 0·001), high CD38 expression (P = 0·02) and unmutated IGHV genes (P = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ≥10% vs <10% prolymphocytes (13% vs 2%) respectively (P < 0·0001). ≥10% prolymphocytes was also associated with a shorter progression‐free survival (Hazard ratio [HR] 1·50 [95% confidence interval [CI]: 1·16–1·93], P = 0·002) and overall survival (HR 1·99 [95% CI: 1·53–2·59], P < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease.     

Diagnosis of CLL revisited: increased specificity by a modified five‐marker scoring system including CD200

The modified Matutes score has been the basis for the diagnosis of chronic lymphocytic leukaemia (CLL) by flow cytometry for the past 15 years. To increase the specificity of the current score we systematically evaluated the diagnostic value of established as well as novel markers, such as CD200, in a large cohort of patients with untreated B‐cell malignancies (n = 370). Double positivity for CD5 and CD23 was of very high value to differentiate between CLL and non‐CLL cases. In addition, lack of FMC7 expression as well as CD79b expression intensity showed high sensitivity (90·4% and 92·3%) with acceptable specificity (74·4% and 76·9%). For surface IgM, low or absent expression displayed poor specificity in distinguishing CLL from non‐CLL cases (51,3%; sensitivity 83,7%). Finally, CD200 positivity showed high sensitivity and specificity. Therefore, CD5/CD23, FMC7, CD79b and CD200 were included in our new CLLflow score, which retained high sensitivity (97·1% vs. 98·6% for the Matutes score, P = 0·38), but showed markedly increased specificity (87·2% vs. 53·8%, P < 0·001). These results were confirmed in our validation cohort (sensitivity 97·0% vs. 100%, P = not applicable; specificity 86·4% vs. 59·1%, P = 0·03). Our data support the use of our new CLLflow score for the diagnosis of CLL with significantly higher specificity.     

In chronic lymphocytic leukaemia with complex karyotype,major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics

Complex karyotype (CK) is a negative prognostic factor in chronic lymphocytic leukaemia (CLL). However, CK is a heterogeneous cytogenetic category. Unbalanced rearrangements were present in 73·3% of 90 CLL patients with CK (i.e. ≥3 chromosome aberrations in the same clone), and were associated with a shorter overall survival (P = 0·025) and a shorter time to first treatment (P = 0·043) by multivariate analysis. Patients with unbalanced rearrangements presented a distinct mRNA expression profile. In conclusion, CLL patients with unbalanced rearrangements might represent a subset of very high‐risk CLL patients with distinct clinical and biological characteristics.     

Long‐term follow‐up of patients receiving allogeneic stem cell transplant for chronic lymphocytic leukaemia: mixed T‐cell chimerism is associated with high relapse risk and inferior survival

There is limited information regarding the immunological predictors of post‐allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T‐cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post‐alloSCT and the ability of post‐transplant immunomodulation to treat relapse. Mixed T‐cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post‐alloSCT; upon 3‐ and 6‐month landmark analysis, this was associated with inferior progression‐free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P < 0·001] and survival (HR 1·66, P = 0·05 and HR 2·17, P < 0·001), independent of baseline patient characteristics, and a lower rate of grade II–IV acute graft‐versus‐host disease (GHVD) (16% vs. 52%, P < 0·001). Thirty‐three patients were treated with immunomodulation for relapse post‐alloSCT (immunosuppression withdrawal, n = 6, donor lymphocyte infusion, n = 27); 17 achieved complete response (CR), which predicted superior PFS (53 months vs. 10 months, P < 0·001) and survival (117 months vs. 30 months, P = 0·006). Relapsed patients with mixed chimerism had inferior response to immunomodulation; conversion to full donor chimerism was highly correlated both with CR and with the development of severe acute GVHD, which was fatal in 3/8 patients. Novel therapeutic strategies are required for patients with mixed T‐cell chimerism post‐alloSCT for CLL.     

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations

In chronic lymphocytic leukaemia (CLL), caution is warranted regarding the clinical implications of immunoglobulin variable heavy chain region (IGHV) rearrangements with a ‘borderline’ (BL) percentage of mutations (i.e. 97–97·9% IGHV identity). We analysed the IGHV mutational status in 759 untreated CLL patients (cohort 1). BL-CLL (n = 36, 5%) showed a time to first treatment (TFT) similar to that of M-CLL (n = 338) and significantly longer than that of UM-CLL (n = 385), despite the enrichment in subset #2 cases. In fact, CLLs belonging to subset #2 (n = 15/759, 2%) were significantly more frequent among BL-CLLs (n = 5/36, 14%), with a brief TFT. TFT of BL-CLL remained comparable to that of M-CLL also considering the 327 CLL patients evaluated at diagnosis. These findings were then validated in an independent cohort 2 of 759 newly diagnosed CLL patients (BL-CLL: n = 11, 1·4%) and in all newly diagnosed patients from cohorts 1 and 2 (n = 1 086, 84% stage A; BL-CLL: n = 47, 4·3%). BL-CLL at diagnosis showed a biological profile comparable to that of M-CLL with a low frequency of unfavourable prognostic markers, except for a significant enrichment in subset #2. Our data suggest that the prognosis of BL-CLL is good and similar to that of M-CLL, with the exception of subset #2 cases.     

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia,even in patients with early stage disease

Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high‐resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere ‘fusogenic’ range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P < 0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI] = 11·6–106·4) and this was preserved in early‐stage disease patients (P < 0·0001, HR=19·3, 95% CI = 17·8–802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high‐resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.     

Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients

This study correlated somatic mutation results and known prognostic factors with time-to-first treatment (TTFT) in 384 treatment-naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease-specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29-gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High-risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.     

Humoral immune failure defined by immunoglobulin class and immunoglobulin G subclass deficiency is associated with shorter treatment‐free and overall survival in Chronic Lymphocytic Leukaemia

Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment‐free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL.     

MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity

Recurrent mutations in MYD88 have been identified in >90% of lymphoplasmacytic lymphoma (LPL). Recently, WHIM (warts, hypogammaglobulinaemia, infections, myelokathexis) syndrome‐like mutations in CXCR4 have been described in 28% of LPL cases, and seem to impact clinical presentation and response to therapy. We investigated the presence of the MYD88 L265P mutation in 90 decalcified, formalin‐fixed, paraffin‐embedded (FFPE) bone marrow (BM) biopsies, including 51 cases of LPL, 14 cases of B‐cell chronic lymphocytic leukaemia (CLL), 13 cases of marginal zone lymphoma (MZL) and 12 normal controls. In addition, the C‐terminal domain of CXCR4 was sequenced in LPL cases. MYD88 L265P was found in 49/51 (96%) LPL cases and in 1/13 (7·6%) MZL (splenic type), whereas all CLL samples remained negative. The two MYD88 wild type LPL cases were associated with cold agglutinin disease. Mutations in CXCR4 were detected in 17/47 (36·2%) LPL cases, which showed a higher extent of BM infiltration and lower leucocyte counts (P = 0·02), haemoglobin (P = 0·05) and platelet counts (P = 0·01). In conclusion the detection of MYD88 L265P mutation in FFPE samples is reliable and useful for subtyping small B‐cell lymphomas in BM biopsies. In addition, the presence of CXCR4 mutations identifies a subgroup of LPL patients with higher disease activity.     

Subjects with chronic lymphocytic leukaemia‐like B‐cell clones with stereotyped B‐cell receptors frequently show MDS‐associated phenotypes on myeloid cells

An increasing body of evidence suggests the potential occurrence of antigen encounter by the cell of origin in chronic lymphocytic leukaemia (CLL) and CLL‐like monoclonal B‐cell lymphocytosis (MBL). However, the scenario in which this event might occur remains unknown. In order to gain insight into this scenario we investigated the molecular, cytogenetic and haematological features of 223 CLL‐like (n = 84) and CLL (n = 139) clones with stereotyped (n = 32) versus non‐stereotyped (n = 191) immunoglobulin heavy chain variable region (IGHV) amino acid sequences. Overall, stereotyped CLL‐like MBL and CLL clones showed a unique IGHV profile, associated with higher IGHV1 and lower IGHV3 gene family usage (P = 0·03), longer IGHV complementary determining region 3 (HCDR3) sequences (P = 0·007) and unmutated IGHV (P < 0·001) versus non‐stereotyped clones. Whilst the overall size of the stereotyped B‐cell clones in peripheral blood did not appear to be associated with the CLL‐related cytogenetic profile of B‐cells (P > 0·05), it did show a significant association with the presence of myelodysplastic syndrome (MDS)‐associated immunophenotypes on peripheral blood neutrophils and/or monocytes (P = 0·01). Altogether our results point to the potential involvement of different selection forces in the expansion of stereotyped vs. non‐stereotyped CLL and CLL‐like MBL clones, the former being potentially favoured by an underlying altered haematopoiesis.     

CD49d (ITGA4) expression is a predictor of time to first treatment in patients with chronic lymphocytic leukaemia and mutated IGHV status

We investigated CD49d (also termed ITGA4) expression and its biological and clinical correlations in 415 patients with chronic lymphocytic leukaemia. CD49d expression was stable over the course of the disease. A high expression of CD49d (>30%) was found in 142/415 (34%) patients and was associated with progressive disease (advanced clinical stage, high serum lactate dehydrogenase or β₂‐microglobulin levels; all p < 0·05) and aggressive disease biology (increased ZAP70 or CD38, unmutated IGHV, trisomy 12, mutations of NOTCH1 and SF3B1; all P < 0·05). A higher CD49d expression was also associated with a lower blood lymphocyte count and a higher number of lymphoid areas involved by the disease. Patients with high CD49d expression were treated more frequently (55% vs. 27%; P < 0·001) and earlier (median time to treatment [TTT] 65·4 months vs. not reached; P < 0·001) than those with low CD49d expression. However, no significant differences in response rates were observed. In the subgroup of patients with mutated IGHV, high CD49d expression was predictive of a shorter TTT while other markers, such as ZAP70 and CD38, were not. In conclusion, in this study CD49d expression correlated with high‐risk CLL biomarkers and proved to be useful for separating patients with mutated IGHV into two different prognostic groups.     

Substratification of patients with newly diagnosed standard-risk multiple myeloma

Despite the absence of high-risk cytogenetics and lower International Staging System (ISS) stages, a subset of patients with multiple myeloma (MM) experience poor overall survival (OS). We studied 1461 patients with newly diagnosed MM to identify patient and disease characteristics that predict a high-risk phenotype among standard-risk patients. Fifty-six percent of all patients presented with standard-risk disease. Among them, advanced age, extremes of body mass index, non-hyperdiploid karyotype and abnormal lymphocyte counts were associated with worse OS. Standard-risk patients with 0–1 of these adverse factors (hazard ratio [HR] 0·32, 95% confidence interval [CI] 0·24–0·43, P < 0·001) and 2 adverse factors (HR 0·54, 95% CI 0·41–0·72, P < 0·001) experienced better OS than high-risk patients. Two or more adverse factors were present in 17% of standard-risk patients and were associated with OS comparable to high-risk patients (HR 0·91, 95% CI 0·67–1·24, P = 0·548). Predictive power among standard-risk patients was improved using score groups compared to ISS stages. Patients with standard-risk MM are a heterogeneous group with one in six patients experiencing OS comparable to high-risk disease. Patients at risk can be identified using readily available patient and disease characteristics. These findings emphasize the importance of accurate risk stratification and help explain part of the heterogeneity observed in clinical practice.     

Ofatumumab retreatment and maintenance in fludarabine‐refractory chronic lymphocytic leukaemia patients

There are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti‐CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24·1 months vs. 6·8 months; time to next therapy was 14·8 months vs. 12·3 months; and progression‐free survival was 7·4 months vs. 7·9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1–2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile.