Hans Pruijt

The influence of micrometastases on prognosis and survival in stage I-II colon cancer patients: the Enroute⊕ Study.

BackgroundThe presence of lymph node metastases remains the most reliable prognostic predictor and the gold indicator for adjuvant treatment in colon cancer (CC). In spite of a potentially curative resection, 20 to 30% of CC patients testing negative for lymph node metastases (i.e. pN0) will subsequently develop locoregional and/or systemic metastases within 5 years. The presence of occult nodal isolated tumor cells (ITCs) and/or micrometastases (MMs) at the time of resection predisposes CC patients to high risk for disease recurrence. These pN0micro+ patients harbouring occult micrometastases may benefit from adjuvant treatment. The purpose of the present study is to delineate the subset of pN0 patients with micrometastases (pN0micro+) and evaluate the benefits from adjuvant chemotherapy in pN0micro+ CC patients.Methods/designEnRoute+ is an open label, multicenter, randomized controlled clinical trial. All CC patients (age above 18 years) without synchronous locoregional lymph node and/or systemic metastases (clinical stage I-II disease) and operated upon with curative intent are eligible for inclusion. All resected specimens of patients are subject to an ex vivo sentinel lymph node mapping procedure (SLNM) following curative resection. The investigation for micrometastases in pN0 patients is done by extended serial sectioning and immunohistochemistry for pan-cytokeratin in sentinel lymph nodes which are tumour negative upon standard pathological examination. Patients with ITC/MM-positive sentinel lymph nodes (pN0micro+) are randomized for adjuvant chemotherapy following the CAPOX treatment scheme or observation. The primary endpoint is 3-year disease free survival (DFS).DiscussionThe EnRoute+ study is designed to improve prognosis in high-risk stage I/II pN0 micro+ CC patients by reducing disease recurrence by adjuvant chemotherapy.Trial RegistrationClinicalTrials.gov: NCT01097265

Successful Transfer of Umbilical Cord Blood CD34+ Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients

Purpose: Older acute myeloid leukemia (AML) patients have a poor prognosis; therefore, novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting a unique scalable NK-cell product generated ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPC) from partially HLA-matched umbilical cord blood units. Experimental Design: Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30 × 106/kg body weight) after lymphodepleting chemotherapy without cytokine boosting. Results: HSPC-NK cell products contained a median of 75% highly activated NK cells, with <1 × 104 T cells/kg and <3 × 105 B cells/kg body weight. HSPC-NK cells were well tolerated, and neither graft-versus-host disease nor toxicity was observed. Despite no cytokine boosting being given, transient HSPC-NK cell persistence was clearly found in peripheral blood up to 21% until day 8, which was accompanied by augmented IL15 plasma levels. Moreover, donor chimerism up to 3.5% was found in bone marrow. Interestingly, in vivo HSPC-NK cell maturation was observed, indicated by the rapid acquisition of CD16 and KIR expression, while expression of most activating receptors was sustained. Notably, 2 of 4 patients with minimal residual disease (MRD) in bone marrow before infusion became MRD negative (<0.1%), which lasted for 6 months. Conclusions: These findings indicate that HSPC-NK cell adoptive transfer is a promising, potential “off-the-shelf” translational immunotherapy approach in AML. Clin Cancer Res; 23(15); 4107–18. ©2017 AACR.

Low dose clofarabine in combination with a standard remission induction in patients 18-60 years with previously untreated intermediate and bad risk acute myeloid leukemia or high risk myelodysplastic syndrome: combined Phase I/II results of the EORTC/GIMEMA AML-14A Trial.

Citation: Selleslag D, Suciu S, Meloni G, Muus P, Halkes CJM, Venditti A, Ramadan SM, Pruijt H, Meert L, Vignetti M, Marie JP, Wittnebel S, de Witte T, Amadori S, Willemze R, and Baron F. Low dose clofarabine in combination with a standard remission induction in patients 18-60 years with previously untreated intermediate and bad risk acute myeloid leukemia or high risk myelodysplastic syndrome: combined Phase I/II results of the EORTC/GIMEMA AML-14A Trial. Haematologica. 2016; 101:xxx doi:10.3324/haematol.2016.153130

Deciding on adjuvant chemotherapy for elderly patients with stage III colon cancer: A qualitative insight into the perspectives of surgeons and medical oncologists

OBJECTIVE The aim of this study is to identify doctor-related factors determining the decision-making for adjuvant chemotherapy for patients with stage III colon cancer aged ≥75years. MATERIALS AND METHODS 21 surgeons and 15 medical oncologists from 10 community hospitals were asked to complete a short questionnaire including tick-box questions regarding motives for non-referral/non-treatment, consultation of geriatricians, chemotherapy schemes prescribed and an open question regarding tolerability of chemotherapy. RESULTS 29 medical specialists returned a completed questionnaire (response 81%). The motives for non-referral/non-treatment reported most often were comorbidity/bad general health condition of the patient; surgical complications; and treatment offered but refused by patient/family. 39% of the surgeons and 55% of the medical oncologists reported consultation of a geriatrician in 2-30% of their decisions. CAPOX and capecitabine were reported by medical oncologists as the most frequently prescribed regimens. Factors that influenced the decision for monotherapy or combination therapy were comorbidity; general health condition of the patient; and toxicity profile of the chemotherapeutics. In general, medical oncologists defined grade ≤2 toxicities as tolerable, with the exception of neuropathy, for which grade ≤1 toxicity was accepted. CONCLUSIONS In case medical oncologists prescribe adjuvant chemotherapy to elderly patients with stage III colon cancer, the chemotherapy schemes used are in line with clinical guidelines and they agree on acceptable levels of toxicity. However, the variation among surgeons and medical oncologists in motives for non-referral, non-treatment and consultation of geriatricians when deciding on adjuvant chemotherapy for elderly patients with stage III colon cancer, shows the complexity and need for specific knowledge.

Multi-center randomized open label phase II trial on three rituximab dosing schemes in immune thrombocytopenia patients.

The overall short-term treatment efficacy of rituximab (R) in immune thrombocytopenia (ITP) is reported to be approximately 58%.[1][1],[2][2] With four once-weekly 375 mg/m2 doses, responses of 31% after two years,[2][2] and 21% after five years[2][2] can be expected with a median clinical

Mild Hypogammaglobulinemia can be a Serious Condition

Background: Most patients with primary antibody deficiency (PAD) suffer from less well-described and understood forms of hypogammaglobulinemia (unclassified primary antibody deficiency, unPAD). Because of the moderately decreased immunoglobulin levels compared to CVID, unPAD is generally considered to be clinically mild and not very relevant. Objective: To describe our cohort of—mainly—unPAD patients, and to analyze whether subgroups can be identified. Methods: Data were prospectively collected (February-2012 to June-2016) as part of a standardized, 1-day Care Pathway for suspected primary immunodeficiency. The TNO-AZL Questionnaire for Health-Related Quality of Life (HRQoL) was part of the pre-first-visit intake procedure. Results: Three hundred and twenty patients were referred to the Care Pathway. Data from 23/27 children and 99/113 adults who were diagnosed with PAD and gave informed consent were available for analysis. 89/99 adults had unPAD, the majority (74%) were female and 44% already showed bronchiectasis. HRQoL was significantly decreased in all domains, meaning that a lot of unPAD patients had to cope simultaneously with pain, negative feelings and impairments in cognition, home management tasks, sleep, social interaction, and work. The most prominently impaired HRQoL domain was vitality, indicating these patients feel extremely tired and worn out. Conclusion: These results highlight the need for more attention to the potential patient burden of unPADs. A larger cohort is needed to increase our understanding of unPADs and to analyze whether distinct subgroups can be identified. For now, it is important for the clinician to acknowledge the existence of unPAD and be aware of its potential consequences, in order to timely and appropriately manage its effects and complications.

The impact of age on first-line systemic therapy in patients with metachronous metastases from colorectal cancer

OBJECTIVES The paucity of evidence for the optimal use of systemic therapy in elderly patients with metastatic colorectal cancer (mCRC) poses significant challenges to cancer specialists. The present population-based study provides insight into the impact of age on palliative systemic therapy in patients with metachronous metastases from CRC, in order to optimize the decision-making process. METHODS Data on the development and treatment of metachronous metastases were collected for patients with primary resected CRC diagnosed between 2003 and 2008 in the Eindhoven area of the Netherlands Cancer Registry. Patients undergoing surgery for metastases were excluded, resulting in a study population treated with palliative intent, with or without systemic therapy (n=746). RESULTS 385 patients received palliative systemic therapy (52%). Patients aged ≥75years were less likely to receive systemic therapy (31% ≥75years vs 73% <60years) and more likely to receive single-agent chemotherapy than combination-chemotherapy. Elderly patients (≥75years) treated with capecitabine-oxaliplatin (CAPOX) received fewer cycles (51% ≤3 oxaliplatin cycles, 43% ≤3 capecitabine cycles) and lower cumulative dosages compared to patients aged <75years, although initial dosages were similar. If capecitabine monotherapy (CapMono) was administered, starting dosages were 2414mg/m2/d<75years and 1992mg/m2/d≥75years (p<0.05), but no differences in number of received cycles or cumulative dosages were observed. CONCLUSION Age beginning at 75years significantly influenced palliative systemic therapy. Even in selected elderly patients, first-line treatment with CAPOX was associated with less cycles and lower cumulative dosages compared to younger patients. With single-agent fluoropyrimidine therapy, however, no such results were observed.

Low-dose clofarabine in combination with a standard remission induction in patients aged 18-60 years with previously untreated intermediate and bad-risk acute myeloid leukemia or high-risk myelodysplastic syndrome: combined phase I/II results of the EORTC/GIMEMA AML-14A trial

Citation: Selleslag D, Suciu S, Meloni G, Muus P, Halkes CJM, Venditti A, Ramadan SM, Pruijt H, Meert L, Vignetti M, Marie JP, Wittnebel S, de Witte T, Amadori S, Willemze R, and Baron F. Low dose clofarabine in combination with a standard remission induction in patients 18-60 years with previously untreated intermediate and bad risk acute myeloid leukemia or high risk myelodysplastic syndrome: combined Phase I/II results of the EORTC/GIMEMA AML-14A Trial. Haematologica. 2016; 101:xxx doi:10.3324/haematol.2016.153130

Low dose clofarabine in combination with a standard remission induction in patients 18-60 years with previously untreated intermediate and bad risk AML or high risk MDS:combined Phase I/II results of the EORTC/GIMEMA AML-14A Trial

Citation: Selleslag D, Suciu S, Meloni G, Muus P, Halkes CJM, Venditti A, Ramadan SM, Pruijt H, Meert L, Vignetti M, Marie JP, Wittnebel S, de Witte T, Amadori S, Willemze R, and Baron F. Low dose clofarabine in combination with a standard remission induction in patients 18-60 years with previously untreated intermediate and bad risk acute myeloid leukemia or high risk myelodysplastic syndrome: combined Phase I/II results of the EORTC/GIMEMA AML-14A Trial. Haematologica. 2016; 101:xxx doi:10.3324/haematol.2016.153130

Phase II study of docetaxel, cisplatin and capecitabine as preoperative chemotherapy in resectable gastric cancer

AIM To investigate the feasibility of preoperative docetaxel, cisplatin and capecitabine (DCC) in patients with resectable gastric cancer. METHODS Patients with resectable gastric cancer fulfilling the inclusion criteria, were treated with 4 cycles of docetaxel (60 mg/m2), cisplatin (60 mg/m2) and capecitabine (1.875 mg/m2 orally on day 1-14, two daily doses) repeated every three weeks, followed by surgery. Primary end point was the feasibility and toxicity/safety profile of DCC, secondary endpoints were pathological complete resection rate and pathological complete response (pCR) rate. RESULTS All of the patients (51) were assessable for the feasibility and safety of the regimen. The entire preoperative regimen was completed by 68.6% of the patients. Grade III/IV febrile neutropenia occurred in 10% of all courses. Three patients died due to treatment related toxicity (5.9%), one of them (also) because of refusing further treatment for toxicity. Of the 45 patients who were evaluable for secondary endpoints, four developed metastatic disease and 76.5% received a curative resection. In 3 patients a pCR was seen (5.9%), two patients underwent a R1 resection (3.9%). CONCLUSION Four courses of DCC as a preoperative regimen for patients with primarily resectable gastric cancer is highly demanding. The high occurrence of febrile neutropenia is of concern. To decrease the occurrence of febrile neutropenia the prophylactic use of granulocyte colony-stimulating factor (G-CSF) should be explored. A curative resection rate of 76.5% is acceptable. The use of DCC without G-CSF support as preoperative regimen in resectable gastric cancer is debatable.