Gunnar Juliusson

Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia

The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.

Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma

Twenty‐three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200u2003mg/d, and 20 patients had dose escalations up to 400 (nu2003=u20035), 600 (nu2003=u200312) or 800u2003mg/d (nu2003=u20033), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR; nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3u2003weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine–doxorubicin–dexamethasone (VAD)‐based treatment in all but one and high‐dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31u2003d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23u2003weeks (range 15–50u2003weeks). Sedation was common but usually tolerable, and some patients continued full‐ or part‐time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.

The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach

Allogeneic haematopoietic stem-cell transplantation (HSCT) is frequently applied as part of the treatment in patients with acute myeloid leukaemia (AML) in their first or subsequent remission. Allogeneic HSCT reduces relapse, but nonrelapse mortality and morbidity might counterbalance this beneficial effect. Here, we review recent studies reporting new disease-specific prognostic markers, in addition to allogeneic-HSCT-related risk factors, which can be assessed at specific time points during treatment. We propose risk assessment as a dynamic process during treatment, incorporating both disease-related and transplant-related factors for the decision to proceed either to allogeneic HSCT or to apply a nontransplant strategy. We suggest that allogeneic HSCT might be favoured if the projected disease-free survival is expected to improve by at least 10% based on an individuals risk assessment. The approach requires initial disease risk assessment, identifying a sibling or unrelated donor soon after diagnosis and the incorporation of time-dependent risk factors, all within the context of an integrated therapeutic management approach.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

BACKGROUNDnCompared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma.nnnMETHODSnThis double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883.nnnFINDINGSnFrom January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group.nnnINTERPRETATIONnMonthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma.nnnFUNDINGnNordic Cancer Union and Novartis Healthcare.

Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival.

Combination chemotherapy may induce remission from acute myeloid leukemia (AML), but validated criteria for treatment of elderly are lacking. The remission intention (RI) rate for elderly patients, as reported to the Swedish Leukemia Registry, was known to be different when comparing the six health care regions, but the consequences of different management are unknown. The Leukemia Registry, containing 1672 AML patients diagnosed between 1997 and 2001, with 98% coverage and a median follow-up of 4 years, was completed with data from the compulsory cancer and population registries. Among 506 treated and untreated patients aged 70–79 years with AML (non-APL), there was a direct correlation between the RI rate in each health region (range 36–76%) and the two-year overall survival, with no censored observations (6–21%) (χ2 for trend=11.3, P<0.001; r2=0.86, P<0.02, nonparametric). A 1-month landmark analysis showed significantly better survival in regions with higher RI rates (P=0.003). Differences could not be explained by demographics, and was found in both de novo and secondary leukemias. The 5-year survival of the overall population aged 70–79 years was similar between the regions. Survival of 70–79-year-old AML patients is better in regions where more elderly patients are judged eligible for remission induction.

Impact of age on survival after intensive therapy for multiple myeloma: a population-based study by the Nordic Myeloma Study Group.

The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60u2003years is not clear. We evaluated the impact of age (<60u2003years vs. 60–64u2003years) on survival in a prospective, population‐based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population‐based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta‐2‐microglobulin and age <60u2003years vs. 60–64u2003years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66u2003months vs. 43u2003months, Pu2003<u20030·001) and 60–64u2003years (median 50u2003months vs. 27u2003months; Pu2003=u20030·001). We conclude that in a population‐based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60–64u2003years but with less superiority than in younger patients.

Subcutaneous alemtuzumab vs ATG in adjusted conditioning for allogeneic transplantation: influence of Campath dose on lymphoid recovery, mixed chimerism and survival.

Sixty-nine consecutive patients (median age 54 years) were prospectively enrolled in a single-institution protocol for allogeneic transplantation with adjusted non-myeloablative fludarabine–melfalan-based conditioning including cyclosporin A and MMF, and one of three modes of serotherapy. Thirty-one donors (45%) were unrelated. The first cohort of 29 had ATG (Thymoglobulin 2u2009mg/kg × 3 days), the subsequent 26 had Campath 30u2009mg × 3 days subcutaneously, and the final cohort of 14 had 30u2009mg Campath once. The groups were similar as regards age, diagnosis and risk factors. Campath-patients had no acute toxicity, fewer days with fever and antibiotics, and required fewer transfusions than ATG-treated patients. 3-d-Campath patients showed lower lymphocyte counts from day +4, and CD4+, CD8+, CD19+ and NK cells recovered slower than in ATG-treated patients. More Campath patients developed mixed chimerism that required DLI. 3-d-Campath induced more serious and opportunistic infections than ATG, which resulted in a greater non-relapse mortality and an impaired overall survival despite a low tumor-related mortality. The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3-d-Campath on immune recovery, severe infections and survival. Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity, but dose limitation to 30u2009mg once is recommended.

Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study

Summary.u2002 Cladribine has single‐drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara‐CTP) of cytosine arabinoside (ara‐C). To evaluate the feasibility of adding intermittent cladribine to intermediate‐dose ara‐C (1u2003g/m2/2u2003h) b.i.d. for 4u2003d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60u2003years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty‐three patients (median 71u2003years, range 60–84u2003years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17u2003d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8u2003d with fever over 38°C, and 17u2003d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two‐drug therapy (Pu2003=u20030·014). The median survival with a 2‐year follow‐up was 14u2003months, and the 2‐year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population‐based approach, the overall results are encouraging.

A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia

The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate.Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10 mg/kg per 24 h in combination with daunorubicin 45 mg/m(2) for 3 days and cytarabine 1 g/m(2) twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients.

Long-term Endoscopic Remission of Crohn Disease after Autologous Stem Cell Transplantation for Acute Myeloid Leukaemia

A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation, and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.