Raija Silvennoinen

Acute lymphoblastic leukemia in adolescents and young adults in Finland

Recent reports indicate that adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric rather than adult therapeutic protocols. This Finnish study did not show any major difference between patients treated with pediatric protocols and those treated with adult protocols, but confirmed that adolescents and young adults with acute lymphoblastic leukemia still have a poorer outcome than children below 10 years of age. See related perspective article on page 1124. Background Interest has recently been paid to adolescents and young adults with acute lymphoblastic leukemia, particularly because all reports so far published indicate that these patients have a better outcome when treated with pediatric rather than adult therapeutic protocols. There are different biological subtypes of acute lymphoblastic leukemia with distinct features and prognoses; the distribution of these subtypes is not well known among adolescents. We, therefore, studied acute lymphoblastic leukemia in adolescents and young adults aged 10 to 25 years in Finland. Design and Methods This population-based study included 225 consecutive patients aged 10–25 years diagnosed with acute lymphoblastic leukemia during 1990–2004. One hundred and twenty-eight patients (10–16 years) were treated with pediatric Nordic (NOPHO) protocols, and 97 patients (17–25 years) with Finnish Leukemia Group National protocols. We characterized the biological subtypes, clinical features and outcome of these patients. Results For the whole cohort, the remission rate was 96%, 5-year event-free survival 62% and overall survival 72%.The 5-year event-free survival was 67% for the pediatric treatment group and 60% for the adult treatment group (p=n.s.). Patients with inferior outcome were those with a white bood cell count ≥ 100×109/L, the Philadelphia chromosome and MLL. Good prognostic features were TEL-AML1, hyperdiploidy, and pediatric intermediate risk stratification. Conclusions Unlike all previous studies, we found that the outcome of adolescents and young adults with acute lymphoblastic leukemia treated with pediatric or adult therapeutic protocols was comparable. The success of the adult acute lymphoblastic leukemia therapy emphasizes the benefit of central referral of patients to academic centers and adherence to research protocols. Key words: acute lymphoblastic leukemia, adolescents, survival, treatment outcome, young adults.

CD34+ cell subclasses and lymphocyte subsets in blood grafts collected after various mobilization methods in myeloma patients

BACKGROUND: Cyclophosphamide (CY) combined with granulocyte–colony‐stimulating factor (G‐CSF) is commonly used to mobilize stem cells in multiple myeloma (MM). Plerixafor may also be used with G‐CSF in patients who mobilize poorly or it may be added to chemomobilization to boost mobilization. Limited data are available on graft content collected after various mobilization methods.

Blood stem cell mobilization and collection in patients with chronic lymphocytic leukaemia: a nationwide analysis

Some reports suggest that blood stem cell mobilization is difficult in a proportion of patients with CLL. We evaluated this issue in a large cohort of CLL patients. One hundred and twenty-eight patients with CLL underwent blood stem cell mobilization during 1995–2005 in Finland. Ninety-five percent of the patients had received fludarabine. The most common mobilization regimen was intermediate-dose CY plus G-CSF (90 patients, 70%). At least 2 × 106/kg CD34+ cells were collected after the first mobilization attempt in 83 patients (65%), whereas 45 patients (35%) failed to reach this collection target. No differences were observed between these patient groups with regard to age, time from the diagnosis to mobilization, number of previous treatment lines, number of fludarabine courses, time from the last fludarabine-containing chemotherapy to mobilization, disease status or degree of marrow infiltration. Patients who failed collection had platelets <100 × 109/l more commonly at the time of mobilization (30 vs 4%, P<0.001). A significant proportion of patients with CLL were difficult to mobilize. Adequate marrow function including platelet counts >100 × 109/l seem to be important factors in terms of successful blood stem cell collection.

Long-term outcome of intensive chemotherapy for adults with de novo acute myeloid leukaemia (AML): the nationwide AML-92 study by the Finnish Leukaemia Group.

Objective:  To investigate the long‐term outcome of idarubicin‐ and cytarabine‐based intensive chemotherapy in adult acute myeloid leukaemia (AML).

Comparative analysis of minimal residual disease detection by multiparameter flow cytometry and enhanced ASO RQ-PCR in multiple myeloma

Multiparameter flow cytometry (MFC) and allele-specific oligonucleotide real-time quantitative PCR (ASO RQ-PCR) are the two most sensitive methods to detect minimal residual disease (MRD) in multiple myeloma (MM). We compared these methods in 129 paired post-therapy samples from 22 unselected, consecutive MM patients in complete/near complete remission. Appropriate immunophenotypic and ASO RQ-PCR-MRD targets could be detected and MRD analyses constructed for all patients. The high PCR coverage could be achieved by gradual widening of the primer sets used for clonality detection. In addition, for 13 (55%) of the patients, reverse orientation of the ASO primer and individual design of the TaqMan probe improved the sensitivity and specificity of ASO RQ-PCR analysis. A significant nonlinear correlation prevailed between MFC-MRD and PCR-MRD when both were positive. Discordance between the methods was found in 32 (35%) paired samples, which were negative by MFC-MRD, but positive by ASO RQ-PCR. The findings suggest that with the described technique, ASO RQ-PCR can be constructed for all patients with MM. ASO RQ-PCR is slightly more sensitive in MRD detection than 6−10-color flow cytometry. Owing to technical demands ASO RQ-PCR could be reserved for patients in immunophenotypic remission, especially in efficacy comparisons between different drugs and treatment modalities.

A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma.

The most common means of mobilizing autologous stem cells is G-CSF alone or combined with cyclophosphamide (CY) to obtain sufficient CD34+ cells for one to two transplants. There are few prospective, randomized studies investigating mobilization regimens in multiple myeloma (MM), especially after lenalidomide-based induction. We designed this prospective, randomized study to compare low-dose CY 2 g/m2+G-CSF (arm A) and G-CSF alone (arm B) after lenalidomide-based up-front induction in MM. Of the 80 initially randomized patients, 69 patients were evaluable, 34 and 35 patients in arms A and B, respectively. The primary end point was the proportion of patients achieving a yield of ⩾3 × 106/kg CD34+ cells with 1−2 aphereses, which was achieved in 94% and 77% in arms A and B, respectively (P=0.084). The median number of aphereses needed to reach the yield of ⩾3 × 106/kg was lower in arm A than in arm B (1 vs 2, P=0.035). Two patients needed plerixafor in arm A and five patients in arm B (P=0.428). Although CY-based mobilization was more effective, G-CSF alone was successful in a great majority of patients to reach the defined collection target after three cycles of lenalidomide-based induction.

Blood graft cellular composition and posttransplant recovery in non-Hodgkin's lymphoma patients mobilized with or without plerixafor: a prospective comparison

Autologous stem cell transplantation is commonly used to treat non‐Hodgkins lymphomas (NHLs). Cellular composition of the blood grafts apparently has a role in the posttransplant hematologic and immune recovery. Plerixafor increases the mobilization of CD34+ cells and higher amounts of various lymphocyte subsets have been reported in the grafts. Limited prospective data are available in regard to graft cellular composition, hematologic and immune recovery, and patient outcomes in NHL patients who receive plerixafor added to chemomobilization.

Assessment of molecular remission rate after bortezomib plus dexamethasone induction treatment and autologous stem cell transplantation in newly diagnosed multiple myeloma patients

Bhatla, D., Davies, S.M., Shenoy, S., Harris, R.E., Crockett, M., Shoultz, L., Smolarek, T., Bleesing, J., Hansen, M., Jodele, S., Jordan, M., Filipovich, A.H. &Mehta, P.A. (2008) Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome. Bone Marrow Transplantation, 42, 159–165. Boocock, G.R., Morrison, J.A., Popovic, M., Richards, N., Ellis, L., Durie, P.R. & Rommens, J.M. (2003) Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nature Genetics, 33, 97–101. Calado, R.T., Graf, S.A., Wilkerson, K.L., Kajigaya, S., Ancliff, P.J., Dror, Y., Chanock, S.J., Lansdorp, P.M. & Young, N.S. (2007) Mutations in the SBDS gene in acquired aplastic anemia. Blood, 110, 1141–1146. Finch, A.J., Hilcenko, C., Basse, N., Drynan, L.F., Goyenechea, B., Menne, T.F., Gonzalez Fernandez, A., Simpson, P., D’Santos, C.S., Arends, M.J., Donadieu, J., Bellanne-Chantelot, C., Costanzo, M., Boone, C., McKenzie, A.N., Freund, S.M. & Warren, A.J. (2011) Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes ShwachmanDiamond syndrome. Genes & Development, 25, 917–929. Hollink, I.H., van den Heuvel-Eibrink, M.M., Arentsen-Peters, S.T., Pratcorona, M., Abbas, S., Kuipers, J.E., van Galen, J.F., Beverloo, H.B., Sonneveld, E., Kaspers, G.J., Trka, J., Baruchel, A., Zimmermann, M., Creutzig, U., Reinhardt, D., Pieters, R., Valk, P.J. & Zwaan, C.M. (2011) NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood, 118, 3645–3656. Johnson, A.W. & Ellis, S.R. (2011) Of blood, bones, and ribosomes: is Swachman-Diamond syndrome a ribosomopathy? Genes & Development, 25, 898–900. Kuijpers, T.W., Alders, M., Tool, A.T., Mellink, C., Roos, D. & Hennekam, R.C. (2005) Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship. Blood, 106, 356–361. Majeed, F., Jadko, S., Freedman, M.H. & Dror, Y. (2005) Mutation analysis of SBDS in pediatric acute myeloblastic leukemia. Pediatric Blood & Cancer, 45, 920–924. Nakashima, E., Mabuchi, A., Makita, Y., Masuno, M., Ohashi, H., Nishimura, G. & Ikegawa, S. (2004) Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome. Human Genetics, 114, 345–348. Shimamura, A. (2006) Shwachman-Diamond syndrome. Seminars in Hematology, 43, 178–188.

Oral treatment of acute myeloid leukaemia with etoposide, thioguanine, and idarubicin (ETI) in elderly patients: a prospective randomised comparison with intravenous cytarabine, idarubicin, and thioguanine in the second and third treatment cycle

A randomised multicentre study was conducted among patients over 65 yr of age with newly diagnosed acute myeloid leukaemia (AML) to compare oral treatment with etoposide 80 mg/m2 and thioguanine 100 mg/m2 twice daily on 5 d and idarubicin 15 mg/m2 on 3 d (ETI) to a mainly i.v. combination of cytarabine 100 mg/m2 twice daily on 5 d, idarubicin 12 mg/m2 × 1 , and thioguanine (TAI). Ninety‐two patients were enrolled. Their median age was 72 yr, range 65–84 yr. Sixty‐five patients had de novo AML, 21 AML subsequent to myelodysplastic syndrome, and six treatment‐related AML. They received at first a 6‐d i.v. treatment with cytarabine and idarubicin. After the first treatment, 68 patients were randomised to receive two cycles of ETI (n = 36) or TAI (n = 32) and thereafter maintenance with mercaptopurine and methotrexate. Of the 92 patients, 52 (57%) achieved remission at some stage. The median survival was 10 months. There were no significant differences between the patients randomised to ETI or TAI in the remission rate (67% vs. 72%), survival (12 months from randomisation in both arms), event‐free survival or relapse rate. The patients randomised to receive ETI spent significantly fewer days at hospital during the two randomised cycles (20 vs. 41 d, P = 0.010), and they had fewer days with infusions, shorter neutropenias and thrombocytopenias and fewer and less severe infections. In conclusion, treatment with oral ETI resulted in a similar antileukaemic effect as obtained with mainly i.v. TAI, with less toxicity and reduced need for hospitalisation.

Identification of precision treatment strategies for relapsed/ refractory multiple myeloma by functional drug sensitivity testing

Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4;14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM.Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4;14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM.