Y.T. Goh

Risk of hepatitis B reactivation and the role of novel agents and stem-cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection

BACKGROUND The purpose of the study is to analyse the prevalence of hepatitis B virus (HBV) infection and its incidence of reactivation among multiple myeloma (MM) patients treated in the era of novel therapy in an endemic Asian setting. PATIENTS AND METHODS From 2000 to 2008, 273 patients with newly diagnosed MM were screened for the presence of hepatitis B virus surface antigen and HBV core antibody. HBV-infected patients were prospectively followed for reactivation with serial monitoring of serum alanine transferase and HBV DNA load. The patterns of HBV reactivation in relation to treatment received, exposure to high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) and novel agents were studied. RESULTS The prevalence of HBV infection was 5.5%. Three cases of HBV reactivation despite lamivudine prophylaxis were reported. Two patients reactivated 3-5 months after HDT/ASCT while receiving thalidomide maintenance and one reactivated 3 years after HDT/ASCT and shortly after bortezomib salvage therapy. Emergence of a mutant HBV strain was documented in one patient. CONCLUSIONS Use of prophylaxis may reduce but will not preclude HBV reactivation. Highest risk occurs during immune reconstitution phase of HDT/ASCT. The role of immunomodulatory agents in HBV reactivation needs to be further elucidated. Separate HBV prophylaxis and surveillance guidelines ought to be developed for patients with MM.

A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation

Summary:We initiated a randomized study of amifostine (the organic thiophosphate formerly known as WR-2721) given to patients during myeloablative conditioning therapy for allogeneic bone marrow transplantation. Amifostine was given at a dose of 1000 mg/day of conditioning and was well tolerated if attention was given to serum calcium levels, blood pressure and antiemetics. Since August 1998, 60 patients (30 on each arm) have completed the study. There was no significant difference in the days to neutrophil or platelet engraftment in either arm of the study. Significantly, the duration of grade I–IV mucositis was decreased in the group that received amifostine (P=0.02). Also grade III or IV infections (P=0.008), duration of antibiotic therapy (P=0.03) and duration of fever (P=0.04) were significantly reduced with amifostine. However, there were no differences in the incidence of grade III or IV mucositis, liver toxicity or renal toxicity. There were also no differences in early mortality, relapse and long-term survival. We conclude that amifostine, while reducing the duration of mucositis and infections (possibly through some preservation of gut mucosal integrity), has a modest effect in allogeneic bone marrow transplants given the multiplicity of factors influencing organ toxicity and survival in this setting.

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era.

Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high‐risk features of myeloma, the validity of conventional risk‐stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long‐term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high‐risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation. Am. J. Hematol., 2010.

Successful treatment of primary granulocytic sarcoma by non-myeloablative stem cell transplant

Pre-leukemic granulocytic sarcoma (GS) may pose an initial diagnostic problem and its therapeutic approach has never been formally established. To our knowledge, non-myeloablative stem cell transplantation has been reported in cases of leukemic GS, but not in primary GS. We report a case of primary GS with extensive and aggressive presenting features and successfully treated with intensive chemotherapy followed by non-myeloablative allogeneic stem cell transplant. This resulted in complete remission with minimal complications. Our case demonstrates the potential of graft-vs.-tumour effect in the treatment of GS and suggests that non-myeloablative allogeneic stem cell transplant may be a feasible therapeutic approach for primary GS.

Severe conidiobolomycosis complicating induction chemotherapy in a patient with acute lymphoblastic leukaemia

The patient, a 20-year-old male, was a full-time soldier and actively involved in field training when diagnosed with acute lymphoblastic leukaemia. Induction chemotherapy, consisting of vincristine, cyclophosphamide, adriamycin and dexamethasone, was given together with itraconazole 200 mg q.i.d. as fungal prophylaxis. He became neutropenic 13 d after commencing chemotherapy and on d15, developed acute onset of right facial and cervical swelling associated with stridor, which required endoscopic-guided intubation to protect his airways. A contrast-enhanced computed tomography (top left) showed the presence of a large right paratonsillar abscess with inflammatory response extending to the right masseter and parotid spaces, resulting in airway obstruction. He subsequently developed a collapse of the entire left lung because of an obstructive plaque in the left main stem bronchus (top right). A bronchoscopic biopsy of the lesion was initially suggestive of aspergillus tracheobronchitis and empirical treatment with caspofungin was commenced, as the concomitant occurrence of acute renal failure and ischemic hepatitis precluded the use of amphotericin or voriconazole. The patient made a striking recovery and was extubated 4 d later with an associated recovery of neutrophils. However, the correct diagnosis was only established when the causative organism was identified as Conidiobolus coronatus. Microscopically (bottom), sporangiola producing secondary multiplicative spores were seen. Conidiobolus coronatus is a saprophyte in soil or organic debris in a tropical environment and typically causes localized nasal and soft tissue infections in animals and rarely in humans. There is still no consensus on the most appropriate anti-fungal treatment. The social background of a patient may play an important role in the pathogenesis of opportunistic infections in an immunocompromised host.

Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in cytogenetic remission in a patient with chronic myeloid leukemia in blast crisis

Summary:The main obstacles to successful hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in blast crisis (BC) are increased post-transplant relapse and high treatment-related mortality. We report a patient with CML in BC who was treated initially with imatinib mesylate and was then concurrently treated with a nonmyeloablative stem cell transplant. Successful engraftment of donor cells followed by complete cytogenetic remission was achieved in the absence of severe therapy-related toxicities. This case demonstrates that imatinib mesylate given through nonmyeloablative transplant is a minimally toxic therapeutic approach, which does not compromise engraftment and may result in a favorable outcome in patients with CML in BC.

Effect of missing killer-immunoglobulin-like receptor ligand in recipients undergoing HLA full matched, non-T-depleted sibling donor transplantation: a single institution experience of 151 Asian patients.

This retrospective analysis studied the impact of natural killer (NK) alloreactivity based on the missing ligand model, for a cohort of recipients undergoing haemopoietic stem cell transplant without T-cell depletion from HLA full-matched sibling donors. All patients received a uniform myeloablative conditioning regimen and prophylaxis for GVHD. A total of 151 patients were studied, including 62 patients with AML or myelodysplastic syndrome, 42 patients with ALL and 47 patients with CML. We found that 81% of patients had at least one missing KIR-ligand (KIR-L), and HLA-C1 allogroup homozygosity is present in 70% of patients. From multivariate analysis, we observed that the only consistently significant factor that was associated with superior survival was disease stage. Missing KIR-L, whether considering HLA-Bw and HLA-C alleles, without or with HLA-A ligands or narrowing to only HLA-C alleles alone to classify the number of missing KIR-L, did not have any impact on OS or relapse-free survival. This negative finding implies that as the KIR-L composition of recipient is not important in this matched non-T-depleted setting, further immunotherapeutic measures involving adoptive NK cell infusions have to be explored to exploit the benefit of NK alloreactivity for such transplants.

Successful Treatment of Idiopathic Hypereosinophilic Syndrome with Imatinib Mesylate : A Case Report

Patients with idiopathic hypereosinophilic syndrome (HES) show persistent hypereosinophilia of unknown etiology that is associated with end-organ damage. Different treatments, including the use of corticosteroids and cytotoxics, have been investigated for HES with modest success. We describe a patient with HES who had significant end-organ damage from hypereosinophilia and remained refractory to conventional therapy. Therapy with imatinib mesylate, a selective tyrosine kinase inhibitor that is highly effective in treating patients with BCR-ABL-positive chronic myeloid leukemia, was tried with the patient. The result was impressive, with hematologic remission achieved after 12 days of administration. Our finding concurs with recent reports that imatinib mesylate may be a promising agent in the treatment of some cases of HES.

Attainment of at least a very good partial response after induction treatment is an important surrogate of longer survival for multiple myeloma

The importance of achieving a very good partial response or better (⩾VGPR) after induction treatment of myeloma has traditionally only been discussed in the context of high-dose therapy with auto-SCT (HDT/auto-SCT). Of late, the advent of novel agents for induction treatment has resulted in improved CR and VGPR rates, which are comparable with those observed with HDT/auto-SCT. We show that in an unselected group of 179 myeloma patients with diverse baseline characteristics, and treated with different modern induction regimens within a single institution, the attainment of ⩾VGPR with or without HDT/auto-ASCT represents a major surrogate marker of better clinical outcomes. On the basis of a 1-year landmark survival analysis, patients achieving ⩾VGPR enjoy a significantly longer PFS, which translated to a longer OS. Superseding the adverse effects of advanced age, high International Staging System (ISS) stage, adverse cytogenetics and independent of the transplant status, the attainment of ⩾VGPR emerged as the single most significant predictor of long-term survival on multivariate analysis.

Severe acute graft-versus-host disease occurring after syngeneic BMT for AML in a patient not given prior cyclosporin A therapy.

A syndrome akin to graft-versus-host disease in the recipient of syngeneic stem cells is hitherto described as being milder, self-limiting and confined to the skin. It is enhanced by prior cyclosporin A therapy. We describe here a recipient of a syngeneic marrow transplant who did not receive priming with cyclosporin A and yet developed severe and progressive graft-versus-host disease which necessitated and responded to high-dose immunosuppressive therapy. We believe that this is because the conditioning regimen in stem cell transplant acts to reset the immune system enabling it to recognise ‘self’ antigens. Bone Marrow Transplantation (2000) 25, 205–207.