Jane Tighe

Guidelines for the use of imaging in the management of myeloma

In 2001, reference to the use of imaging in the British Committee for Standards in Haematology guidelines for the diagnosis and management of myeloma was confined to the standard use of plain X‐rays in the diagnostic skeletal survey and emergency use of computed tomography (CT) and magnetic resonance (MR) imaging in the setting of cord compression. Since then, there has been a steady rise in interest in the use of various imaging techniques in the management of myeloma. The purpose of imaging in the management of myeloma includes the assessment of the extent and severity of the disease at presentation, the identification and characterisation of complications, and the assessment of response to therapy. Plain radiography, CT, and MR imaging are generally established examination techniques in myeloma whilst positron emission tomography (PET) and 99Technetium sestamibi (MIBI) imaging are promising newer scanning techniques under current evaluation. These stand‐alone imaging guidelines discuss recommendations for the use of each modality of imaging at diagnosis and in the follow up of patients with myeloma.

A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

Leukemic and Non-Leukemic Lymphocytes from Patients with Li Fraumeni Syndrome Demonstrate Loss of p53 Function, Bcl-2 Family Dysregulation and Intrinsic Resistance to Conventional Chemotherapeutic Drugs But Not Flavopiridol

Li Fraumeni syndrome (LFS) is characterised by a predisposition to the early onset of certain tumors and is associated with germline mutation of the anti-oncogene p53. In this study we analysed the in vitro responses of lymphocytes from two LFS patients to chemotherapeutic drugs in terms of apoptosis induction and the expression of key intracellular proteins that regulate this process. One of the LFS patients also suffered from B-cell chronic lymphocytic leukemia (B-CLL) and hence presented with a light-chain restricted B-cell lymphocytosis while the other patient had entirely normal blood counts. The B-lymphocytes from both LFS patients showed a marked degree of resistance to chlorambucil and fludarabine when compared to age-matched controls but were remarkably sensitive to the novel flavone, flavopiridol. Loss of function of p53 was demonstrated by a failure to induce Bax and p21 protein expression. In addition, altered basal expression patterns of Bcl-2 and Bax, two key regulators of apoptosis, were found in the LFS lymphocytes when compared with controls. These results suggest that LFS lymphocytes carrying a p53 mutation show intrinsic resistance to conventional chemotherapeutic drugs and this is associated with dysregulation of Bcl-2 family proteins. Furthermore, The innate resistance profile was similar in leukemic and non-leukemic lymphocytes and was therefore independent of genetic changes acquired during malignant transformation. Novel agents that induce p53-independent cell killing may be useful not only in the treatment of LFS-associated tumors but also drug resistant tumors in general where p53 and/or Bcl-2 family dysregulation is a feature.

Optimizing the management of patients with spinal myeloma disease

Myeloma is one of the most common malignancies that results in osteolytic lesions of the spine. Complications, including pathological fractures of the vertebrae and spinal cord compression, may cause severe pain, deformity and neurological sequelae. They may also have significant consequences for quality of life and prognosis for patients. For patients with known or newly diagnosed myeloma presenting with persistent back or radicular pain/weakness, early diagnosis of spinal myeloma disease is therefore essential to treat and prevent further deterioration. Magnetic resonance imaging is the initial imaging modality of choice for the evaluation of spinal disease. Treatment of the underlying malignancy with systemic chemotherapy together with supportive bisphosphonate treatment reduces further vertebral damage. Additional interventions such as cement augmentation, radiotherapy, or surgery are often necessary to prevent, treat and control spinal complications. However, optimal management is dependent on the individual nature of the spinal involvement and requires careful assessment and appropriate intervention throughout. This article reviews the treatment and management options for spinal myeloma disease and highlights the value of defined pathways to enable the proper management of patients affected by it.

Myeloid leukaemic cells can lyse fibrin directly

Purified preparations of circulating leukaemic blast cells from patients with acute myeloid (M1–7) or acute lymphoblastic leukaemia, and the myeloid or lymphoid cells from patients with chronic myeloid or lymphocytic forms of leukaemia, were incorporated into clots prepared from fibrinogen and plasminogen. Patterns of lysis were followed and measured by light transmission in a microtitre plate reader. Mature polymorphonuclear and mononuclear cell fractions from normal individuals were studied concurrently for comparison. Blast cells from the myeloid forms of acute leukaemia (M2–4) and ‘myeloid’ cell fractions from patients with chronic myeloid leukaemia were capable of lysing plasminogen‐containing clots; this activity was neutralized by addition of immunoglobulin against urokinase plasminogen activator (u‐PA), but not by anti‐tissue plasmogen activator (t‐PA). Mature polymorphonuclear and mononuclear cells from normal individuals lacked lytic activity, as did the leukaemic cells from patients with acute lymphoblastic or chronic lymphocytic leukaemia. Lysed blast cells showed the presence of free plasminogen activator on sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS–PAGE) with overlay zymography, also neutralized by anti‐u‐PA, whereas normal polymorphonuclear and mononuclear cells did not. These observations suggest that mechanisms underlying some forms of severe bleeding in acute myeloid leukaemias have a critical fibrinolytic component generated by the blast cells themselves.

Re‐transplantation after bortezomib‐based therapy

Whilst the use of high dose alkylating agents and autologous stem cell transplantation (ASCT) has a fundamental role in consolidating initial anti-tumour induction therapy, its role in salvage therapy consolidation remains to be determined. Bortezomib has been shown to be an effective agent at first and subsequent relapse, with responses equivalent or better than the response to previously used conventional therapies in first-line therapy (Richardson et al, 2005; Laubach et al, 2009). Combining bortezomib re-induction with a second ASCT after maximal anti-tumour response is, therefore, an attractive concept. Accordingly, we undertook a retrospective review of patients proceeding to a second ASCT after bortezomib-based re-induction therapy. Patients undergoing a second ASCT after progression from an initial ASCT and subsequent bortezomib re-induction therapy in 12 centres were identified (n = 40). Detailed information on the patients was obtained through anonymized clinical data retrieval forms, capturing critical patient and disease-specific factors including response to initial induction therapy, response to first ASCT, time to progression, subsequent therapies, bortezomib-based re-induction therapy and response to second ASCT (including the type of transplant and stem cell source). Response to therapy was categorized according to the International Myeloma Working Group criteria (Durie et al, 2006). Kaplan Meier plots were made using the Statistical Package for the Social Sciences (spss) IBM, Chicago, Illinois, USA. There were insufficient cytogenetic data for analysis. A total of 40 patients were identified in this retrospective study. Two patients had planned reduced intensity allogeneic (RIC-Allo) transplants after their second autologous transplant and weren excluded from further analysis. Patient characteristics including age, sex, type of myeloma, therapy prior to their first and second transplants are shown in Table Ia. One patient who relapsed 10 months after their bortezomib therapy was transplanted in relapse. All other patients were transplanted prior to disease progression. Twenty-six patients were treated with a combination of bortezomib and dexamethasone, eight patients had PAD chemotherapy (bortezomib, adriamycin and dexamethasone (Oakervee et al, 2005). Two patients had bortezomib monotherapy, one patient had bortezomib plus intravenous melphalan and one patient had bortezomib plus cyclophosphamide, dexamethasone and idarubicin. The median number of cycles of bortezomib therapy was 4 (range 2–12). Patients receiving PAD chemotherapy also had a median of four cycles

Bilateral cerebellopontine angle lesions not always NF2: diagnostic pitfall

Abstract Bilateral internal auditory canal (IAC) tumours are almost exclusively associated with bilateral vestibular schwannomas, and there is very little, if anything, that can mimic this appearance. We present a very rare case of a 75-year-old gentleman who initially presented with bilateral IAC tumours and later diagnosed as an isolated primary CNS myeloma without systemic involvement. This is a very rare presentation and has important diagnostic and therapeutic implications. He was treated with a combination of lenalidomide and dexamethasone. The treatment was well tolerated but with limited response. Although rare, metastasis should be considered as a differential diagnosis of IAC lesions.

Safety and efficacy of pulsed imatinib with or without G‐CSF versus continuous imatinib in chronic phase chronic myeloid leukaemia patients at 5 years follow‐up

Despite their efficacy in inducing deep and durable responses in chronic phase (CP) chronic myeloid leukaemia (CML) patients, BCR-ABL1 tyrosine kinase inhibitors (TKI) do not eradicate leukaemia stem cells (LSC), as proven by the persistence of BCR-ABL1+ CD34+, colony forming, longterm culture-initiating cells in the bone marrow of patients in sustained molecular response 4 5 (a 4 5-log reduction of BCR-ABL1 transcript levels, MR4 5) following TKI therapy (Chomel et al, 2011). CML LSC survival is independent of BCR-ABL1 kinase activity (Hamilton et al, 2012) and their quiescence is a putative TKI-resistance mechanism causing disease persistence. Moreover TKI exert anti-proliferative rather than pro-apoptotic effects against CML LSCs and might further contribute to disease persistence (Graham et al, 2002). Promoting LSC cellcycle entry using granulocyte-colony stimulating factor (G-CSF) has been shown in vitro to restore their sensitivity to TKI and enhance their eradication (Jorgensen et al, 2006). Based on this evidence, we performed a randomized phase II study (GIMI, EudraCT 2004-000179-33), which compared the safety and efficacy of continuous imatinib (cIM) versus pulsed imatinib (pIM) alone or with G-CSF (pIM+G) therapy administered in 4-week cycles for 48 weeks (12 cycles in total) in CP CML patients with at least a complete cytogenetic response (CCyR) on IM (Drummond et al, 2009) (see reference for study design, primary and secondary endpoints, patient demographics and disease characteristics). The experimental arms were expected to improve CML LSCs eradication by reducing TKI-induced quiescence (pIM) and/or by actively pushing CML LSCs into cell-cycle (pIM+G). At 2 years follow-up no statistically significant differences for the study endpoints were observed, possibly due to the limited numbers (15 patients per arm). However, 6/30 patients across the two experimental arms exhibited either loss of CCyR or major molecular response (MMR) as compared with only 1/15 in the cIM arm, with all but one patient in the experimental arms regaining MMR on restarting continuous IM or nilotinib therapy (Drummond et al, 2009). These results raised some concerns that the experimental schedules might have contributed to the loss of response. Subsequently, a mathematical model of the safety and efficacy of the IM and G-CSF combination suggested that this approach might be detrimental in the shortto mediumterm for patients with persistent disease treated with IM, by increasing the LSCs burden through enhanced proliferation, thus in turn increasing the risk of acquiring a resistance mutation and of disease progression. However, in the longterm (>2500 d, i.e. 6 8 years, from start of treatment), such an approach was predicted to prove beneficial as it would deplete the CML LSCs by increasing their susceptibility to TKI (Foo et al, 2009). Here we report the 5-year follow-up data for the GIMI study. 41/45 patients were available for analysis; four patients had died (one only as a result of CML progression). The median follow-up was 5 67 years. Using an intention to treat analysis, both CCyR and MMR rates were similar among treatment arms with no differences in progression rates. 5/15 patients in the cIM arm compared to 3/15 patients in each experimental arm changed treatment to second generation TKI (Table I).

Pulmonary hypertension in POEMS syndrome: resolution following radiotherapy

Pulmonary hypertension (PH) is defined by the presence of a mean pulmonary artery pressure (mPAP) ≥25 mmHg. It may be idiopathic or arise as a consequence of a number of diverse conditions. PH has been reported in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes), with reversal following systemic treatment with corticosteroids. We report a case of pulmonary hypertension associated with POEMS syndrome treated with radical radiotherapy locally to bone lesions with resolution of systemic disease.

United Kingdom myeloma forum position statement on the use of lenalidomide in multiple myeloma

Lenalidomide is an immunomodulatory drug, which has anti‐myeloma activity in vitro. Phase II clinical trials have demonstrated lenalidomide in combination with dexamethasone is effective for the treatment of both relapsed refractory myeloma and newly diagnosed patients. Two large phase III studies comparing lenalidomide and dexamethasone to dexamethasone alone in relapsed patients showed superiority in response, progression free and overall survival. It is administered orally for 21 days in a 28 day cycle. Side effects are manageable and include neutropenia and venous thrombotic events. It is currently approved, in combination with dexamethasone, for the treatment of multiple myeloma patients who have received at least one prior therapy. Studies in front line patients and with other drug combinations are ongoing. Given the strength of this data the UK Myeloma Forum believe that lenalidomide in combination with dexamethasone should be available for prescription by UK haematologists according to its licensed indication in patients with relapsed myeloma.