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).

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).

Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial.

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl-1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

A randomized clinical trial on the effectiveness of an intervention to treat psychological distress and improve quality of life after autologous stem cell transplantation.

Psychological distress contributes to impaired quality of life in hematological cancer patients. Stepped care treatment, in which patients start with the least intensive treatment most likely to work and only receive more intensive interventions if needed, could improve distress. We aimed to evaluate the outcome of stepped care treatment on psychological distress and physical functioning in patients treated with autologous stem cell transplantation for hematological malignancies. In the present study, we performed a randomized clinical trial with two treatment arms: stepped care and care as usual. Baseline assessment and randomization occurred during pre-transplant hospitalization. Stepped care was initiated after 6 weeks, consisting of (1) watchful waiting, (2) Internet-based self-help intervention, and (3) face-to-face counseling/ psychopharmacological treatment/ referral. Follow-up measurements were conducted at 13, 30, and 42 weeks after transplantation. Stepped care (n = 47) and care as usual (n = 48) were comparable on baseline characteristics. The uptake of the intervention was low: 24 patients started with step 1, 23 with step 2, and none with step 3. Percentages of distressed patients ranged from 4.1 to 9.7 %. Ten percent of patients received external psychological or psychiatric care. No statistically significant differences were found between stepped care and care as usual on psychological distress or physical functioning in intention to treat analyses, nor in per protocol analyses. The stepped care program was not effective in decreasing psychological distress. The low intervention uptake, probably related to the low levels of psychological distress, offers an explanation for this outcome. Future research should take into account patients' specific care needs. Netherlands Trial Registry identifier: NTR1770.

Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.

The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.

[A man with neutropenic fever]. / Een man met neutropene koorts.

A 43-year-old patient with recurrent acute myeloid leukemia (AML) was treated with high-dose cytarabine. After two weeks of neutropenic fever, multiple cutaneous nodules appeared. Histopathological examination of a skin biopsy showed a mycosis and Fusarium solani was cultured. Despite antimycotic therapy, the patient died due to complications of his AML treatment.

Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial.

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.

Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma.

BACKGROUND: The prognosis of T-cell lymphoma is poor. To explore the addition of the monoclonal antibody alemtuzumab, we studied the efficacy and tolerability of an intensified alemtuzumab-chemotherapy combination for aggressive T-cell lymphoma in a phase II study by Dutch-Belgian Hemato-Oncology Group (HOVON). PATIENTS AND METHODS: Patients (≤65 years) with newly diagnosed T-cell lymphoma received eight CHOP cycles (cyclophosphamide, doxorubicin, vincristine, prednisone) 2-weekly, each cycle with three doses of 30 mg alemtuzumab. Prophylaxis consisted of cotrimoxazole, fluconazole and valaciclovir. Cytomegalovirus (CMV) monitoring took place at least every fortnight. RESULTS: Twenty patients from 10 centers, median age 50 years, were included. Eighty-five percent received six or more cycles. The overall response was 90% [12 complete remissions (CRs), 1 CR unconfirmed, 5 partial remissions]. Median duration of follow-up of patients still alive was 29 months (range 19-41 months). Median overall survival (OS) and event-free survival (EFS) were 27 and 10 months, with 55%/27% OS/EFS at 2 years. Adverse events consisted of neutropenic fever (n = 8) and CMV reactivation (n = 7), with one CMV disease. Three patients developed secondary Epstein-Barr virus (EBV)-related lymphoma, all after end of treatment. CONCLUSIONS: Although intensified alemtuzumab-CHOP induces high responses, many patients relapse, and the scheme is associated with serious infection-related adverse events. EBV monitoring after end of treatment is required.

[Monoclonal B-cell lymphocytosis: physiological entity or preliminary stage of chronic lymphocytic leukaemia?]. / Monoklonale B-cellymfocytose: fysiologische bevinding of voorstadium van chronische lymfatische leukemie?

The criteria for the diagnosis of chronic lymphocytic leukaemia (CLL) have recently been changed, with the absolute number of monoclonal B cells instead of the total number of lymphocytes now important. CLL is diagnosed when the number of monoclonal B cells with the characteristic CLL phenotype in peripheral blood exceeds 5 x 10(9)/l; fewer than 5 x 10(9)/l of monoclonal B cells with the characteristic CLL phenotype present in peripheral blood leads to a diagnosis of monoclonal B-cell lymphocytosis (MBL): a new diagnostic entity. The prevalence of MBL is estimated to be 3% and has a relatively mild course with a progression rate from MBL to CLL of 1-2% per year. After a single evaluation by a haematologist to exclude lymphadenopathy, organomegaly and infection as causes of the lymphocytosis, patients with MBL need only be evaluated once annually by their general practitioner for measurement of the blood lymphocyte count and referral in case of progression.

Failure of CHOP with rituximab for lymphomatoid granulomatosis.

We present a 66-year-old male patient with pulmonary lymphomatoid granulomatosis. The patient had progressive disease after three courses of CHoP and rituximab and, therefore, treatment with interferon-alpha 2b 5 x 10(6) IE three times a week was started. This resulted in stable disease for five months. subsequently, progression occurred and the patient died 12 months after initial presentation. lymphomatoid granulomatosis is a rare, poor-risk, Epstein-Barr virus related, B cell lymphoproliferative disease. There is no standard treatment but promising results have been reported with rituximab, either as monotherapy or in combination with chemotherapy. This case demonstrates that lymphomatoid granulomatosis is still a chemotherapy-resistant disease in some patients despite addition of rituximab. A review of the literature regarding aetiology, clinical features, diagnosis and treatment options is presented.

Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.

Abrupt versus gradual withdrawal of vitamin K antagonist treatment in patients with venous thromboembolic disease: assessment of hypercoagulability and clinical outcome.

BACKGROUND: It is yet unclear whether vitamin K antagonist treatment should be stopped abruptly or gradually after an episode of venous thromboembolism. The mode of withdrawal might influence a potential development of a hypercoagulable state, which could influence the risk for recurrent disease. METHODS: We prospectively studied 37 consecutive patients in whom acenocoumarol was discontinued either abrupt (18) or gradually (19) (2/3 and 1/3 of the initial dose for one week). Blood sampling was performed at various time points up to 18 days after complete withdrawal and was analysed for INR, prothrombin fragment F1 + 2 and D-dimer. All patients were clinically followed-up for the assessment of the association between hypercoagulability and occurrence of disease such as recurrent venous thromboembolism or malignancy. RESULTS: An approximately fourfold increase was observed (median increase from 0.3 to 1.3 nmol/l) in the F1 + 2 levels after both abrupt and gradual withdrawal and in the D-dimer concentrations in the abrupt withdrawal group (0.10 to 0.44 mg/l), while those in whom acenocoumarol was discontinued gradually showed a less pronounced increase of the D-dimer levels (0.11 to 0.29 mg/L) (not significant). During follow-up one recurrent venous thromboembolic event occurred in each group, and a diagnosis of cancer was made four times. All these patients had the highest D-dimer concentrations measured in the entire study group. CONCLUSIONS: This study indicates the potential for a hypercoagulable state after acenocoumarol discontinuation, which was not prevented by tapering the acenocoumarol dose. D-dimer, measured 2 to 3 weeks after acenocoumarol withdrawal, might be an important tool to identify patients at risk for recurrent venous thromboembolism and/or for the presence of an underlying malignancy.

Changes in perfusion scintigraphy in the first days of heparin therapy in patients with acute pulmonary embolism.

Patients with suspected pulmonary embolism often receive heparin therapy for hours to days before ventilation/perfusion scintigraphy is completed. We assessed to what extent the lung scan classification and pulmonary vascular perfusion changed over a period of 2-4 days of full anticoagulant therapy. In 312 consecutive patients with at least one segmental perfusion defect on the initial perfusion scan, classification of both the initial and the final lung scan allowed us to study alteration in scan classification. Changes in pulmonary perfusion were assessed scintigraphically in a subgroup of 64 patients with proven pulmonary embolism. Among 79 patients with an initial high-probability lung scan, the final scan remained high probability in 77 whereas it became non-diagnostic and normal in one patient each. The lung scan classification did not change in any of the 233 patients who initially had a non-diagnostic scan. Thus, a different lung scan category was observed in only 2 out of 312 patients (0.6%; 95% CI 0.1%-2.3%). The mean pulmonary perfusion at baseline in the subgroup of 64 patients with pulmonary embolism was 62% (SD +/-17%; range 26%-89%). A mean absolute improvement in pulmonary perfusion of only 4%+/-11% (NS) was observed in the 2-4 days of observation. It is concluded that intravenous heparin therapy for a period of 2-4 days has only a minimal influence on the diagnostic lung scan classification and induces only minor changes in pulmonary vascular obstruction in the majority of patients.

Reactions and platelet increments after transfusion of platelet concentrates in plasma or an additive solution: a prospective, randomized study.

BACKGROUND: Reactions after platelet transfusions are rather common and frequently are caused by plasma constituents. In recent developments, the preparation and storage of platelet concentrates (PCs) in a platelet additive solution (PAS-2) have been shown to result in acceptable storage conditions. A major drawback of the use of these PCs is the progressive increase of P-selectin-positive platelets during storage. The clinical benefit of transfusions of PCs in PAS-2 was studied. STUDY DESIGN AND METHODS: PCs prepared from buffy coats were suspended in either plasma or PAS-2 and stored for up to 5 days. Clinical responses were evaluated in a prospective study in 21 patients treated with intensive chemotherapy for hematologic malignancies. Eligible patients were randomly assigned to receive prophylactic transfusions of PCs prepared in either plasma or PAS-2. Reactions and CCIs were recorded after each transfusion. RESULTS: The incidence of reactions in 12 patients given PCs in plasma (n = 192) was 12 percent. Transfusions to 9 patients of PCs in PAS-2 (n = 132) showed a reduction in the incidence of reactions to 5.3 percent (p<0.05). The average 1-hour and 20-hour CCIs after transfusion of PCs in plasma were 20.7 +/- 8. 5 and 11.5 +/- 8.0, respectively. CCIs after transfusion of PCs in PAS-2 were significantly lower: the average 1-hour CCI was 17.1 +/- 6.6 (p<0.001) and the average 20-hour CCI was 9.5 +/- 7.0 (p<0.05). Storage conditions of PCs were optimal: in each group, average 1-hour CCIs of both fresh and stored PCs were similar. The 20-hour CCIs after the transfusion of fresh and stored PCs in PAS-2 also were similar. CONCLUSION: Transfusion of PCs in PAS-2 significantly reduces the incidence of reactions. The 1-hour and 20-hour CCIs after transfusion of PCs in PAS-2 were significantly lower than the CCIs after transfusion of PCs in plasma. Because storage conditions of both PCs were found to be optimal, the decrease in CCIs after transfusion of PCs prepared in PAS-2 may be caused by rapid elimination of a subpopulation of P-selectin-positive platelets from the circulation.

Value of chest X-ray combined with perfusion scan versus ventilation/perfusion scan in acute pulmonary embolism.

BACKGROUND: The main purpose of ventilation scanning, as adjunct to perfusion lung scintigraphy, in acute pulmonary embolism is to allow for the classification of segmental perfusion defects as mismatched, which is generally accepted as proof for the presence of pulmonary embolism. We examined whether this function of the ventilation scan could be replaced by the chest X-ray. METHODS: In 389 consecutive patients with suspected pulmonary embolism and at least one segmental perfusion defect we classified the ventilation/perfusion (V/Q) scan and chest X-ray/perfusion (X/Q) scan as either mismatched or matched. Furthermore we analyzed whether this comparison was different in subgroups of patients with concomitant congestive heart failure or chronic obstructive pulmonary disease. RESULTS: Overall agreement between the X/Q and V/Q scan diagnostic category was found in 341 of 389 patients (88%; 95% CI 84-92%). The positive predictive value for obtaining a mismatched V/Q scan result in case of a mismatched X/Q scan result was 86% (95% CI 81-90%). If the X/Q scan yielded only matched defects the V/Q scan resulted in the same classification in 90% (95% CI 85-95%). Analysis of the small subgroup of patients with chronic obstructive pulmonary disease showed that a mismatched X/Q scan was confirmed by V/Q scanning in 21 of 34 cases (62%; 95% CI 45-78%). CONCLUSION: This study shows that in the great majority of patients with clinically suspected acute pulmonary embolism combination of chest X-ray with perfusion scintigraphy reliably replaced ventilation/perfusion scintigraphy in defining (mis)-matching of segmental perfusion defects. These results need confirmation before the chest X-ray can fully obviate the use of ventilation scintigraphy.

The use of a rapid D-dimer blood test in the diagnostic work-up for pulmonary embolism: a management study.

BACKGROUND: D-dimer assays have a potential to rule out pulmonary embolism in case of a normal test result. We studied the clinical utility of incorporating the SimpliRED D-dimer test result and clinical probability in the routine diagnostic work-up of patients with suspected acute pulmonary embolism. METHODS: In a prospective management study 245 consecutive patients, hospitalised as well as outpatients, were included. A SimpliRED D-dimer test and perfusion/(ventilation) scintigraphy were obtained in all patients, whereas clinical probability was determined in the subgroup of patients with a non-diagnostic scan and normal D-dimer result. A diagnostic algorithm determined the necessity for further testing and decisions about treatment. All patients were followed up for 3 months. RESULTS: In 54 patients (22%) with a normal lung scan and 50 patients (21%) with a high probability lung scan, antithrombotic therapy was withheld or started respectively, irrespective of the D-dimer result. A non-diagnostic lung scan was found in 137 (56%) patients, of whom 70 patients had an abnormal D-dimer test, in whom further testing was ordered. Of the remaining 67 patients with a non-diagnostic lung scan and normal D-dimer test 8 patients had a high clinical probability, and the subsequent ultrasonography and pulmonary angiography yielded pulmonary emboli in 1 patient. In the remaining 66 patients, pulmonary embolism was considered to be absent and antithrombotic treatment was stopped/withheld. During follow-up of these patients only one patient experienced a possible venous thromboembolic event (failure rate 1,5%; 95% CI 0-8%). The SimpliRED D-dimer was normal in 6 of 61 patients with proven pulmonary embolism (sensitivity 90%; 95% CI 80-96%). CONCLUSION: Our findings suggest that it is safe to withhold anticoagulant therapy in those patients with a non-diagnostic lung scan, a normal SimpliRED D-dimer test result, and without a high clinical probability. This results in a substantial decreased need for ultrasonography and pulmonary angiography. The SimpliRED should not be used in isolation to exclude pulmonary embolism.