Sathish Kumar Gopalakrishnan

Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development.

Despite the recent major advancement in therapy for multiple myeloma, it remains an incurable disease. There remains an unmet need for novel therapies that target different mechanisms of action. Immunotherapy with monoclonal antibodies is a promising area of development and will expand our therapeutic armamentarium in the fight against myeloma. Daratumumab is a novel, high-affinity, therapeutic human monoclonal antibody against unique CD38 epitope with broad-spectrum killing activity. It has a favorable safety profile as monotherapy in patients with relapsed/refractory myeloma and also demonstrates significant single-agent activity. Abundant preclinical data supports its use in combination therapy and clinical studies on various exciting combinations are underway. This review focuses on the CD38 antigen and its targeting with daratumumab and provides an update on the results of recent clinical studies involving daratumumab.

Early relapse post autologous transplant is a stronger predictor of survival compared with pretreatment patient factors in the novel agent era: analysis of the Singapore Multiple Myeloma Working Group

The clinical outcome of multiple myeloma is heterogeneous. Both the depth of response to induction and transplant as well as early relapse within a year are correlated with survival, but it is unclear which factor is most relevant in Southeast Asian patients with multiple myeloma. We retrospectively analyzed outcomes of 215 patients who were treated with upfront autologous transplant in Singapore between 2000 and 2014. In patients who received novel agent (NA)-based induction, achieving only partial response (PR) post-induction was associated with poorer OS (HR 1.95, P=0.047) and PFS (HR 2.9, P<0.001), while achieving only PR post-transplant was strongly correlated with both OS (HR 3.3, P=0.001) and PFS (HR 7.6, P<0.001), compared with patients who achieved very good partial response (VGPR) or better. Early relapse was detected in 18% of all patients, although nearly half had initially achieved VGPR or better post-transplant. Early relapse after NA-based induction led to significantly shorter OS (median 22 months vs not reached, P<0.001), and was strongly associated with OS (HR 13.7, P<0.001). The impact of suboptimal post-transplant response and early relapse on survival may be more important than pretransplant factors, such as International Staging System or cytogenetics, and should be considered in risk stratification systems to rationalize therapy.

Pre-transplant achievement of negativity in minimal residual disease and French–American–British L1 morphology predict superior outcome after allogeneic transplant for Philadelphia chromosome positive acute lymphoblastic leukemia: an analysis of Southeast Asian patients

Abstract To better understand predictive factors and improve the clinical outcome of allogeneic transplant for patients with Philadelphia positive acute lymphoblastic leukemia, we analyzed 67 Southeast Asian patients transplanted in our institutions. Multivariate analysis showed that disease status before transplant, year of transplant and, interestingly, French–American–British (FAB) subtype had a significant impact on overall survival (OS) and non-relapse mortality. Patients who were minimal residual disease (MRD) negative at transplant had a 3-year OS of 73% compared to those who were MRD positive (45%) and refractory (0%). The 3-year cumulative incidence of relapse was 18% and 36% for the MRD negative and positive groups, respectively. FAB L1 subtype had a significantly superior 3-year OS of 63% vs. 29% for L2 subtype. Pre-transplant use of a tyrosine kinase inhibitor significantly improved outcomes in univariate but not multivariate analysis, as it served to induce more patients into MRD negativity, which was the factor that directly improved transplant outcome.

Subcutaneous bortezomib combined with weekly cyclophosphamide and dexamethasone is an efficient and well tolerated regime in newly diagnosed multiple myeloma

Regimens that combine bortezomib and steroids with thalidomide, lenalidomide or cyclophosphamide have resulted in high response rates and are now considered standard treatments in newly diagnosed, transplant-eligible multiple myeloma (Reeder et al, 2009; Cavo et al, 2010; Richardson et al, 2010). The comparison between bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy is important given the significantly lower drug costs of these regimens compared to bortezomib-lenalidomide-dexamethasone (VRD). We aim to highlight certain aspects of the cyclophosphamide dosing and the route of administration of bortezomib that are crucial in the success of VCD as an upfront treatment regime for multiple myeloma. We read with interest the meta-analysis by Leiba et al (2014), which concluded that patients treated with VTD had significantly higher near complete or complete response (nCR/CR) (34% vs. 6%) and very good partial response (VGPR) or better (62% vs. 27%), compared to VCD-treated patients. Studies included in the VCD arm used heterogeneous regimens with different dosing of cyclophosphamide, and regimens using less cyclophosphamide led to lower CR rates, a point also noted by the authors (Leiba et al, 2014). In particular, support for a higher dosing of cyclophosphamide to deepen response comes from the EVOLUTION trial that achieved better nCR/CR (12% vs. 3%) and ≥ VGPR rates (41% vs. 13%) with an additional dose of cyclophosphamide (Kumar et al, 2012), albeit limited by the small sample size of 17 patients in the higher cyclophosphamide arm. In our institution in Singapore, we routinely use VCD treatment with a higher dosing of cyclophosphamide and subcutaneously administered bortezomib. We retrospectively analysed 46 transplant-eligible patients in our hospital with newly diagnosed symptomatic multiple myeloma who were initiated on VCD treatment (Table I). Treatment consisted of 28-d cycles of bortezomib, given subcutaneously at a concentration of 1 3 mg/m on days 1, 8, 15 and 22, oral cyclophosphamide at 500 mg on days 1, 8, 15and 22, and oral dexamethasone at 40 mg on days 1, 8, 15 and 22. All patients had prophylaxis with co-trimoxazole and acyclovir. The primary endpoint was the best response at the end of VCD therapy prior to transplant. The number of cycles used, and dose modification for haematological or non-haematological toxicities were at the discretion of the treating physician. Responses were assessed according to the International Myeloma Working Group (IMWG) criteria (Durie et al, 2006). Using the intensified regimen of VCD with additional cyclophosphamide and subcutaneous bortezomib led to high response rates with a favourable side-effect profile. 39% of Table I. Patient baseline characteristics and response.

Daratumumab improves the anti-myeloma effect of newly emerging multidrug therapies

Correspondence: Daryl Tan Raffles Cancer Center, 585 North Bridge Road, #13-00, Raffles Hospital, Singapore 188770, Republic of Singapore Tel +65 6311 2300 Fax +65 6311 1181 Email tan_daryl@rafflesmedical.com; daryl.tan@sgh.com.sg Abstract: Although the clinical outcomes of patients with multiple myeloma has improved tremendously with the advent of bortezomib and immunomodulatory drugs like thalidomide and lenalidomide, the disease remains incurable and patients will eventually be resistant to these drugs. Novel non-cross-resistant modalities of treatment are needed. Immunotherapy is potentially a very promising therapeutic modality for further development. Daratumumab is a novel, high-affinity, therapeutic human monoclonal antibody against a unique CD38 epitope. It induces tumor-cell killing through several immunological mechanisms. It has shown a favorable safety profile as monotherapy and significant single-agent activity in relapsed/refractory myeloma. It has also demonstrated strong synergism with lenalidomide and bortezomib. The potential of this agent, together with its pharmacokinetics, mode of action, early efficacy, and safety data will be detailed in this review.

Occult recurrence of monomorphic epitheliotropic intestinal T-cell lymphoma and the role of MATK gene expression in diagnosis

Monomorphic epitheliotropic intestinal T‐cell lymphomas (MEITL), formerly Type II enteropathy‐associated T‐cell lymphomas (EATL), are rare peripheral T‐cell lymphomas. They are associated with poor survival outcomes, in part because of their late diagnosis. Although MEITLs may be reliably diagnosed based on histological and immunophenotypic findings, overlaps with other NK/T and T‐cell lymphomas may confound the diagnosis. The distinctive high‐level nuclear staining of the novel marker Megakaryocyte‐associated tyrosine kinase (MATK) in MEITLs is an invaluable tool in distinguishing MEITL from classical EATL and other NK/T or T‐cell lymphomas. 18‐Fluorine‐2‐fluorodeoxyglucose positron emission tomography (18F‐FDG PET) has been shown to be a useful tool in the staging and follow‐up of aggressive lymphomas. Herein, we describe an unusual case of occult hepatic recurrence of MEITL that was non‐avid on 18F‐FDG PET, in which diagnosis was confirmed based on the expression of MATK in tumour cells. Copyright

The impact of time from diagnosis to treatment in diffuse large B-cell lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is a high-grade lymphoma that requires treatment. We retrospectively analyzed the impact of time from diagnosis-to-treatment (TDT) on progression-free survival (PFS) and overall survival (OS) in 581 R-CHOP-treated patients. TDT was defined as the interval between diagnostic biopsy date and day 1 R-CHOP. Cox regression showed stage 3–4 disease (p = .01) and longer TDT (HR 1.13, p =.031) were associated with shorter OS. Eastern Cooperative Oncology Group ≥2 (p = .02), stage 3–4 disease (p < .001), and longer TDT (HR 1.12, p = .028) predicted shorter PFS. The significant interactions between TDT with lactate dehydrogenase (LDH) and with disease stage prompted separate analyses in high versus normal LDH, and stage 3–4 versus 1–2 disease. Longer TDT was associated with shortened PFS and OS only with advanced stage, and, if high LDH was present. Treatment should be started as early as possible for high-tumor burden disease. Delaying treatment in patients with early stage or low LDH does not seem harmful.

Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction

&NA; The current standard of care for transplant‐eligible multiple myeloma (MM) patients is novel agent‐based (NA) induction followed by high‐dose chemotherapy and autologous stem cell transplant (ASCT). This study analyzed the efficacy of pegfilgrastim in stem cell (PBSC) mobilization compared to filgrastim, exclusively after NA‐based induction in a homogeneous group of MM patients. We analyzed 89 patients with MM treated at 2 transplant centers in Singapore who received NA‐based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high‐dose melphalan conditioning and ASCT. This study demonstrates that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient of 6 days of filgrastim injections. Background: The current standard of care for transplant‐eligible myeloma patients is novel agent‐based induction, followed by high‐dose chemotherapy and autologous stem cell rescue. Chemo‐mobilization of peripheral blood CD34+ stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained‐duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost‐effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent‐based induction in a homogeneous group of MM patients. Patients and Methods: We analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent‐based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high‐dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 ± 0.84 days for both, and the peak peripheral blood CD34+ stem cell count was 19.90 × 106/kg for pegfilgrastim and 32.50 × 106/kg for filgrastim (95% confidence interval, −4.36 to 0.70 × 106/kg). Results: No significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 × 106/kg vs. filgrastim, 10.10 × 106/kg; P = .16). Conclusion: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy.

Respiratory virus infection after allogeneic hematopoietic stem cell transplant in a tropical center: Predictive value of the immunodeficiency scoring index

Respiratory virus infection (RVI) is a prevalent infection in patients after allogeneic hematopoietic stem cell transplant (allo‐HSCT) and can result in significant morbidity and mortality. Ability to assess the potential severity of RVI is important in the management of such patients.

VALIDATION OF THE CNS INTERNATIONAL PROGNOSTIC INDEX IN A LARGE ASIAN COHORT-DATA FROM THE SINGAPORE LYMPHOMA STUDY GROUP

199 VALIDATION OF THE CNS INTERNATIONAL PROGNOSTIC INDEX IN A LARGE ASIAN COHORT–DATA FROM THE SINGAPORE LYMPHOMA STUDY GROUP Y. Lee* | S.C. Fook‐Chong | A.Z. Goh | C. Nagarajan | N.F. Grigoropoulos | S. Gopalakrishnan | Y. Chen | T.P. Tang | M. Tao | R.H. Quek | L. Khoo | M. Farid | S.T. Lim | Y.T. Goh | C. Phipps Haematology, Singapore General Hospital, Singapore, Singapore; HSRU, Division of Medicine, Singapore General Hospital, Singapore, Singapore; Medical Oncology, National Cancer Centre, Singapore, Singapore