Chemoimmunotherapy for relapsed/refractory and progressive 17p13‐deleted chronic lymphocytic leukemia (CLL) combining pentostatin,alemtuzumab, and low‐dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab‐containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short‐duration regimen combining pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab designed to decrease the risk of treatment‐associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13?) (n = 3). Thirteen (33%) patients had both 17p13? and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty‐six (67%) patients completed therapy, with only five (13%) patients having treatment‐limiting toxicity and no treatment‐related deaths. Twenty‐two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression‐free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B‐cell lymphoma (n = 6). Correlative studies showed that low‐dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab is a tolerable and effective therapy for CLL and that low‐dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. Am. J. Hematol. 89:757–765, 2014. © 2014 Wiley Periodicals, Inc.     

Low‐dose alemtuzumab in refractory/relapsed chronic lymphocytic leukemia: Genetic profile and long‐term outcome from a single center experience

Relapsed/refractory chronic lymphocytic leukemia (CLL) represents a clinical challenge, in particular when high risk gene mutations occur. In this setting, alemtuzumab was recognized to be effective. This retrospective study evaluates long‐term efficacy and tolerability of low‐dose alemtuzumab in relapsed/refractory CLL and correlates clinical outcome with biological feature. Sixty‐two consecutive patients (median age 68 years) were evaluated; alemtuzumab was administered 30 mg weekly for up to 18 weeks. Among the patients included in the analysis, 37% were fludarabine‐refractory, 33.3% carried a TP53 disruption, 14.8% a NOTCH1 mutation and 9% a SF3B1 mutation. Overall response rate (ORR) was 61.3% (complete remission 25.8%). After a median follow‐up of 43 months, overall survival (OS) and progression free survival (PFS) were 43.1 and 15 months, respectively; while ORR was 77.8% for patients carrying TP53 disruptions (OS 33.8 months) and 43.5% for fludarabine‐refractory patients (OS 30 months). Noteworthy, long‐term survivors (OS ≥ 36 months) were 54.8%. None of the biological poor risk factors negatively impacted on ORR, PFS and OS. Grade ≥3 cytopenia occurred in 24.2% patients, 6.5% experienced a grade ≥3 non‐CMV infection and no grade ≥3 CMV‐event occurred. In conclusion, low dose‐alemtuzumab is safe and effective in relapsed/refractory CLL, also in a long‐term follow‐up and high‐risk genetic subgroups. Am. J. Hematol. 90:970–974, 2015. © 2015 Wiley Periodicals, Inc.     

Biological and clinical characterization of recurrent 14q deletions in CLL and other mature B‐cell neoplasms

14q‐deletions have been repeatedly described in mature B‐cell neoplasms, but not yet characterized in a larger cohort. Based on chromosome banding analysis, the present study identified 47 del(14q) cases in 3054 mature B‐cell neoplasms (1·5%) (chronic lymphocytic leukaemia [CLL]: 1·9%; CLL/prolymphocytic leukaemia [PL]: 9·0%; others: 0·2%). Interphase fluorescence in situ hybridization was performed with probes for 14q22.1, 14q24.1, 14q32.33, and IGH@ (14q32.3). The del(14q) had heteregeneous size but showed a breakpoint cluster at the centromeric site in 14q24.1 (62% of cases). At the telomeric side, the most frequent breakpoint was within the IGH@ locus (14q32.3) between IGH@ 3′‐flanking and IGHV (IgVH) probes (45%). In 16 cases (34%), breakpoints occurred within 14q24.1 and 14q32.3. Eighty‐one percent of del(14q) cases showed 1–3 additional cytogenetic alterations (in 45%, +12), and 56% were IGHV‐unmutated. In all cases (16/16) with breakpoints in 14q24.1 and 14q32.3, a B‐CLL immunophenotype was found. Clinical follow‐up in 32 del(14q) patients was compared to 383 CLL and CLL/PL patients without del(14q). While 3‐year‐overall survival did not differ significantly, time to treatment was significantly shorter in the del(14q) cohort (21·0 months vs. 80·1 months, P = 0·015). In conclusion, the del(14q) is a rare recurrent alteration in diverse mature B‐cell neoplasms, shows variable size but distinct clustering of breakpoints, and is associated with short time to treatment.     

F‐18 FDG‐PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem‐cell transplantation for relapsed and refractory Hodgkin lymphoma

Total lymphoid irradiation (TLI) followed by high‐dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high‐dose chemotherapy and aHSCT. Pre‐transplant fludeoxyglucose positron emission tomography (FDG‐PET) studies were scored on the 5‐point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10‐year progression‐free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5‐year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long‐term survival rates for patients with relapsed/refractory HL, including those with high‐risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.     

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.     

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.     

Improved survival for relapsed diffuse large B cell lymphoma is predicted by a negative pre‐transplant FDG‐PET scan following salvage chemotherapy

The utility of ^[18F]fluoro‐2‐deoxy‐ d ‐glucose positron‐emission tomography (FDG‐PET) for predicting outcome after autologous stem cell transplantation (ASCT) for diffuse large B cell lymphoma (DLBCL) is uncertain – existing studies include a range of histological subtypes or have a limited duration of follow‐up. Thirty‐nine patients with primary‐refractory or relapsed DLBCL with pre‐ASCT PET scans were analysed. The median follow‐up was 3 years. The 3‐year progression‐free survival (PFS) for patients with positive PET scans pre‐ASCT was 35% vs. 81% for those who had negative PET scans (P = 0·003). The overall survival (OS) in these groups was 39% and 81% (P = 0·01), respectively. In a multivariate analysis, PET result, number of salvage cycles and the presence of relapsed or refractory disease were shown to predict a longer PFS; PET negativity (P = 0·04) was predictive of a longer OS. PET is useful for defining those with an excellent prognosis post‐ASCT. Although those with positive scans can still be salvaged with current treatments, PET may useful for selecting patients eligible for novel consolidation strategies after salvage therapies.     

Phase I‐II trial of oral cyclophosphamide,prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma

This single institution, open label Phase I‐II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid®), cyclophosphamide and prednisone (CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m² on day 1, 8, and 15, lenalidomide 25 mg on d 1–21 and prednisone 100 mg every other day in a 28‐d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full‐dose CPR regimen produced no dose‐limiting toxicity and was delivered for a median of 16 months (3·5–65 months) with acceptable safety and tolerance. The overall response rate (≥ partial response) was 94% at a median follow up of 28 months. The median progression‐free survival was 16·1 months [95% confidence interval (CI); 10·9–22·5 months], while the median overall survival was 27·6 months (95% CI; 16·8–36·6 months). Only the beta‐2 microglobulin level at protocol entry correlated with a better survival (P = 0·047). These observations compare favourably with other 2‐ and 3‐ drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients.     

Enhanced ex vivo inhibition of platelet function following addition of dipyridamole to aspirin after transient ischaemic attack or ischaemic stroke: first results from the TRinity AntiPlatelet responsiveness (TrAP) study

Ex vivo dipyridamole ‘non‐responsiveness’ has not been extensively studied in ischaemic cerebrovascular disease. Platelet surface marker expression, leucocyte‐platelet complex formation and inhibition of platelet function at high shear stress as detected by the PFA‐100^® Collagen‐Adenosine‐diphosphate (C‐ADP) and Collagen‐Epinephrine cartridges was assessed in 52 patients within 4 weeks of transient ischaemic attack (TIA) or ischaemic stroke on aspirin, and then 14 d (14 d) and >90 d (90 d) after adding dipyridamole. A novel definition of ‘Dipyridamole non‐responsiveness’ was used. The median C‐ADP closure time increased following addition of dipyridamole, remained elevated at 90 d (P ≤ 0·03), and was unaffected by aspirin dose. 59% at 14 d and 56% at 90 d were ‘dipyridamole non‐responders’ on the PFA‐100. The proportion of non‐responders at 14 and 90 d was similar (P = 0·9). Compared with baseline (4·6%), median monocyte‐platelet complexes increased at 14 d (5·0%, P = 0·03) and 90 d (4·9%, P = 0·04). Low C‐ADP closure times were associated with increased monocyte‐platelet complexes at 14 d (r = ?0·32, P = 0·02) and 90 d (r = ?0·33, P = 0·02). Monocyte‐platelet complexes increased in the subgroup of dipyridamole non‐responders on the PFA‐100 (P ≤ 0·045), but not in responders (P ≥ 0·5), at 14 and 90 d versus baseline. Additional inhibition of platelet function has been detected with the PFA‐100 when dipyridamole is added to aspirin. Elevated monocyte‐platelet complexes may contribute to ex vivo dipyridamole non‐responsiveness.     

A phase II,single‐arm,multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B‐cell lymphoma

In this phase II, multicentre, single‐arm study, 52 patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) received the anti‐CD19 antibody–drug conjugate coltuximab ravtansine (55 mg/m²) and rituximab (375 mg/m²) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0–41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2–78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0–72·1%]) or first‐line therapy (15·4% [80% CI: 6·9–28·4%]). Median progression‐free survival, overall survival and duration of response were 3·9 [80% CI: 3·22–3·98], 9·0 [80% CI: 6·47–13·67] and 8·6 (range: 0–18) months, respectively. The pharmacokinetics of both drugs were unaffected by co‐administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL.     

Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis

Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1–15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.     

Predicting thyroxine requirements following total thyroidectomy

Objective Optimal thyroxine replacement following total thyroidectomy is critical to avoid symptoms of hypothyroidism. The aim of this study was to determine the best formula to determine the initiated replacement dose of levothyroxine immediately following total thyroidectomy. Design Prospective study. All patients were initiated on 100 μg levothyroxine and titrated to within the reference range for TSH and free T4. Correlations to height, weight, age, lean body mass (LBM), body surface area (BSA) and body mass index (BMI) were calculated. Patients One hundred consecutive adult patients underwent total thyroidectomy for non‐malignant disease. Measurements Comparison between three methods of levothyroxine dose prediction, aiming for a levothyroxine dose correct to within 25 μg of actual dose required. Results Correlations were seen between levothyroxine dose and patient age (r = ?0·346, P < 0·01), bodyweight (r = 0·296, P < 0·01), LBM (r = 0·312, P < 0·01), BSA (r = 0·319, P < 0·01) and BMI (r = 0·172, P < 0·05). A regression equation was calculated (predicted levothyroxine dose = [0·943 × bodyweight] + [?1·165 × age] + 125·8), simplified to (levothyroxine dose = bodyweight ? age + 125) pragmatically. Initiating patients empirically on 100 μg post‐operatively showed that 40% of patients achieved target within 25 μg of their required dose; this increased to 59% when using a weight‐only dose calculation (1·6 μg/kg) and to 72% using the simplified regression equation. Conclusions A simple calculated regression equation gives a more accurate prediction of initiated levothyroxine dose following total thyroidectomy, reducing the need for outpatient attendance for dose titration.     

Platinum and high‐dose cytarabine‐based regimens are efficient in ultra high/high‐risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study

Ultra high‐risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine‐based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty‐seven patients had R/R CLL (including 36 ultra high‐risk CLL) and 28 had RS. Median age was 62 years (range, 18–79 years). Median number of previous therapies was 3 (range, 1–7), including fludarabine‐based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression‐free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high‐dose cytarabine‐based regimens provide high response rates in high‐risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non‐transformed CLL.     

Clinical activity of a new regimen combining gemcitabine and alemtuzumab in high‐risk relapsed/refractory chronic lymphocytic leukemia patients

Optimal treatment strategies are lacking in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Gemcitabine has shown activity and acceptable safety profile in B‐cell lymphomas. We present a retrospective case review of gemcitabine and alemtuzumab, every 21 d (for up to six courses) in 27 community‐based patients with high‐risk R/R CLL. Median age was 70 yr (44–83 yr), 55% patients had Binet stage C, deletion 17p (del(17p)) and/or deletion 11q (del(11q)) were found in 65% and 27%, bulky disease in 55.5%, and fludarabine‐refractoriness in 48% of cases, respectively. Overall response rate was 63% (29.6% clinical CR and 33.4% PR). At a median follow‐up of 31 months, median PFS and OS were 15.4 and 24 months. In multivariate analysis, median OS is influenced by prior lines of treatment = 3 and bulky disease. Combination of alemtuzumab and gemcitabine appears to be an active, easy to administrate treatment in routine practice, high‐risk R/R CLL patients.     

Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia

Otlertuzumab (TRU ‐016) is a humanized anti‐CD 37 protein therapeutic that triggers direct caspase‐independent apoptosis of malignant B cells and induces antibody‐dependent cell‐mediated cytotoxicity. Patients with relapsed chronic lymphocytic leukaemia (CLL ) received either otlertuzumab (20 mg/kg) weekly by IV infusion for two 28‐day cycles then every 14 days for four 28‐day cycles and IV bendamustine (70 mg/m²) on Days 1 and 2 of each cycle for up to six 28‐day cycles or bendamustine alone. Thirty‐two patients were treated with otlertuzumab and bendamustine and 33 with bendamustine alone. Overall response rate according to the International Workshop on Chronic Lymphocytic Leukaemia criteria was 69% in the otlertuzumab and bendamustine arm and 39% in the bendamustine alone arm (P  = 0·025). Median progression‐free survival (PFS ) was 15·9 months in the otlertuzumab and bendamustine arm and 10·2 months in the bendamustine alone arm (P  = 0·0192). There was a higher incidence of pyrexia (34% vs. 12%) and neutropenia (59% vs. 39%) with the combination but this did not result in a higher incidence of severe (grade 3/4) infections (13% vs. 27%). This combination significantly increased the response rate and prolonged the PFS over single agent bendamustine in patients with relapsed or refractory CLL .     

Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B‐cell malignancies

This phase Ib, dose‐escalation study investigated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and preliminary efficacy of the pan‐class I phosphoinositide 3‐kinase (PI3K) and mechanistic target of rapamycin (mTOR) inhibitor voxtalisib [30 or 50 mg twice daily (BID)], in combination with rituximab (voxtalisib+rituximab) or rituximab plus bendamustine (voxtalisib+rituximab+bendamustine), in relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma (NHL), mantle cell lymphoma and chronic lymphocytic leukaemia (CLL). MTD and RP2D of voxtalisib were determined using a 3 + 3 dose‐escalation design. Adverse events (AEs), plasma PK and disease response were recorded. Thirty‐seven patients were enrolled. The RP2D of voxtalisib in combination with rituximab or rituximab+bendamustine was 50 mg BID. Four patients experienced a total of five dose‐limiting toxicities. The most frequent AEs were nausea (45·9%), fatigue (37·8%) headache (32·4%) and pyrexia (32·4%). The most frequent grade ≥3 AEs were neutropenia (27·0%), thrombocytopenia (24·3%), anaemia (16·2%) and febrile neutropenia (10·8%). Voxtalisib PK parameters were not affected by co‐administration with rituximab or rituximab+bendamustine. Of 35 efficacy‐evaluable patients, four (11·4%) achieved complete response and 13 (37·1%) achieved partial response. Voxtalisib, in combination with rituximab or rituximab+bendamustine, demonstrated an acceptable safety profile and encouraging anti‐tumour activity in relapsed or refractory B‐cell malignancies.     

Salvage therapy using FLT3 inhibitors may improve long‐term outcome of relapsed or refractory AML in patients with FLT3‐ITD

To determine the long‐term efficacy of FLT3 inhibitors (FLT3i) in the salvage setting for relapsed and refractory (rel/ref) acute myeloid leukemia (AML) with FLT3 internal tandem duplication (AML FLT3‐ITD), we conducted a retrospective study of 120 patients with rel/ref AML FLT3‐ITD who received salvage therapy with either FLT3i‐containing regimen (FLT3i group, N = 45) or conventional cytotoxic regimen (conventional group, N = 75). The median overall survival (OS) after the first salvage in the FLT3i group was 6·9 vs. 4·6 months in the conventional group (P = 0·17). The OS was better in the FLT3i group among patients with initial complete remission (CR) duration ≤12 months or with primary refractory disease (6·9 vs. 3·7 months; P < 0·01). The OS was better when FLT3i was combined with cytotoxic agents versus monotherapy (17 vs. 4·8 months; P = 0·017). Multivariate analysis revealed that the use of FLT3i was an independent predictor of OS (hazard ratio 0·58; 95% confidence interval, 0·38–0·88). Incorporating FLT3i into salvage strategies may improve long‐term outcome of patients with AML FLT3‐ITD. Prospective studies to validate this conclusion are warranted.     

Levothyroxine replacement therapy and refractory hypotension out of transitional period in preterm infants

Background Recent studies suggest that refractory hypotension from causes other than septicaemia or cardiac failure is common in extremely preterm infants even out of the transitional period. Marked response to low‐dose cortisol suggests underlying adrenal insufficiency, although the exact mechanism remains unknown. Methods To investigate potential triggers for and related short‐term outcomes of early‐onset (n = 7) was correlated with younger gestational ages <26 weeks (P < 0·05), whereas the incidence of late‐onset refractory hypotension (n = 14) was correlated with younger gestational ages and levothyroxine supplementation (P < 0·05 and 0·01, respectively). The incidence of both early‐ and late‐onset refractory hypotension was correlated with risks of short‐term adverse outcomes such as prolonged mechanical ventilation and hospital stay. Conclusions Levothyroxine supplementation was identified as an independent variable correlated with an increased incidence of refractory hypotension out of the transitional period; as seen in hypothyroidism with Addison’s disease, the immature hypothalamic‐pituitary‐adrenal axis may not respond properly to the increased demand for cortisol, which may precipitate premature infants into refractory hypotension. Following the administration of levothyroxine, preterm infants may have to be carefully monitored for early signs of refractory hypotension.     

A phase II randomized trial comparing standard and low dose rituximab combined with alemtuzumab as initial treatment of progressive chronic lymphocytic leukemia in older patients: a trial of the ECOG‐ACRIN cancer research group (E1908)

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti‐CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8‐12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m² weekly)(n = 16) or low dose (20 mg/m² 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression‐free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti‐CD20 mAb therapy as a potentially more effective use of anti‐CD20 mAb in the treatment of CLL. Am. J. Hematol. 91:308–312, 2016. © 2015 Wiley Periodicals, Inc.     

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.