Ae Virchis

Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes.

The combination of fludarabine (FDR), high dose cytarabine and granulocyte colony stimulating factor (FLAG) with or without idarubicin (Ida) was used in the treatment of poor risk acute leukaemia or myelodysplastic syndrome (MDS) in a single centre experience. A total of 105 patients were treated over a 4‐year period with 59% achieving a complete remission (CR); no statistical difference observed between FLAG and FLAG‐Ida. For patients responding to FLAG ± Ida, the median event‐free survival (EFS) was 11 months and 23% at 5 years. Such patients proceeded either to further chemotherapy or a haematopoietic stem cell transplant (HSCT). The median EFS (13 months vs. 8 months) and projected 5‐year survival (37% vs. 13%) of patients undergoing HSCT was significantly better than those who did not (P = 0.021). In all, 14 of 72 patients remain alive in continuing CR (median duration 43 months) with 10 of 31 having had a HSCT vs. four of 41 that did not (P = 0·033). Both regimens were well tolerated, with the majority of patients experiencing grade 1 or less non‐haematological toxicity (mainly nausea and vomiting). The median time to neutrophil and platelet recovery was 28 and 31 d, respectively. No significant differences were seen with the addition of ida. There was a 17% incidence of treatment‐related deaths, of which 39% was caused by invasive aspergillus infection. The results show that FLAG ± Ida is an effective and well‐tolerated remission induction regimen for poor risk leukaemia and MDS.

Primary splenic hairy cell leukaemia variant presenting as immune thrombocytopenic purpura

The disease now known as hairy cell leukaemia (HCL) is a chronic B-cell leukaemia accounting for approximately 2% of adult leukaemia. It was first described as a distinct clinical entity by Bouroncle et al. in 1958 (1) and termed leukaemic reticuloendotheliosis. The term hairy cell leukaemia was coined by Schrek & Donnelly in 1966 (2). In 1980 a rare variant of HCL (HCL-V) was first described (3) and subsequently further cases have been reported, the largest series being from The Royal Marsden Hospital (4). Primary splenic HCL is another very rare entity (5-8) suggesting that the malignant cell in HCL may originate in the spleen. However, to date there have been no reported cases of primary splenic HCL-V. We describe a case of apparent primary splenic HCL-V, presenting as immune thrombocytopenic purpura (ITP), in which splenectomy resulted in both clinical and haematological remissions. This adds further support to the hypothesis that the spleen is the site of origin of these disorders.

Ofatumumab is a feasible alternative anti-CD20 therapy in patients intolerant of rituximab

Awan, F.T., Flynn, J.M., Jones, J.A., Andritsos, L.A., Maddocks, K.J., Sass, E.J., Lucas, M.S., Chase, W., Waymer, S., Ling, Y., Phelps, M.A., Byrd, J.C., Lucas, D.M. & Woyach, J.A. (2015) Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma. Leukemia & lymphoma, 56, 2834–2840. Cheson, B.D., Pfistner, B., Juweid, M.E., Gascoyne, R.D., Specht, L., Horning, S.J., Coiffier, B., Fisher, R.I., Hagenbeek, A., Zucca, E., Rosen, S.T., Stroobants, S., Lister, T.A., Hoppe, R.T., Dreyling, M., Tobinai, K., Vose, J.M., Connors, J.M., Federico, M. & Diehl, V. (2007) International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. Journal of Clinical Oncology, 25, 579– 586. Faderl, S., Rai, K., Gribben, J., Byrd, J.C., Flinn, I.W., O’Brien, S., Sheng, S., Esseitine, D.L. & Keating, M.J. (2006) Phase II study of singleagent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. Cancer, 107, 916–924. Goy, A., Bernstein, S.H., Kahl, B.S., Djulbegovic, B., Robertson, M.J., de Vos, S., Epner, E., Krishnan, A., Leonard, J.P., Lonial, S., Nasta, S., O’nor, O.A., Shi, H., Boral, A.L. & Fisher, R.I. (2009) Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated timeto-event analyses of the multicenter phase 2 PINNACLE study. Annals of Oncology, 20, 520– 525. Lendvai, N., Hilden, P., Devlin, S., Landau, H., Hassoun, H., Lesokhin, M.A., Tsakos, I., Redling, K., Koehne, G., Chung, D.J., Schaffer, W.L. & Giralt, S.A. (2014) A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood, 124, 899–906. O’Connor, O.A., Stewart, A.K., Vallone, M., Molineaux, C.J., Kunkel, L.A., Gerecitano, J.F. & Orlowski, R.Z. (2009) A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clinical Cancer Research, 15, 7085–7091. Richardson, P.G., Briemberg, H., Jagannath, S., Wen, P.Y., Barlogie, B., Berenson, J., Singhal, S., Siegel, D.S., Irwin, D., Schuster, M., Srkalovic, G., Alexanian, R., Rajkumar, S.V., Limentani, S., Alsina, M., Orlowski, R.Z., Najarian, K., Esseltine, D., Anderson, K.C. & Amato, A.A. (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. Journal of Clinical Oncology, 24, 3113–3120. Robak, T., Huang, H., Jin, J., Zhu, J., Liu, T., Samoilova, O., Pylypenko, H., Verhoef, G., Siritanaratkul, N., Osmanov, E., Alexeeva, J., Pereira, J., Drach, J., Mayer, J., Hong, X., Okamoto, R., Pei, L., Rooney, B., van de Velde, H. & Cavalli, F.; LYM-3002 Investigators. (2015) Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. The New England journal of medicine, 372, 944–953. Rule, S. (2016) Frontline therapy and role of highdose consolidation in mantle cell lymphoma. Hematology American Society of Hematology Education Program, 1, 419–424. Zhang, L., Pham, L.V., Newberry, K.J., Ou, Z., Liang, R., Qian, J., Sun, L., Bionska, M., You, Y., Yang, J., Lin, X., Rollo, A., Tamayo, A.T., Lee, J., Ford, R.J., Zhao, X., Kwak, L.W., Yi, Q. & Wang, M. (2013) In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: targeting the immunoproteasome. Molecular cancer therapeutics, 12, 2494–2504.

RNA-Seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.