Summary:Cardiotoxicity has rarely been reported as a complication of melphalan or fludarabine administration as single agents. Recently, melphalan and fludarabine have been used in combination as non-myeloablative conditioning chemotherapy prior to allogeneic stem cell transplantation. We have observed the development of severe left ventricular failure in three of 21 patients treated with this combination. Cardiotoxicity in this context has not previously been reported and has implications for the assessment, monitoring and treatment of patients undergoing pre-transplant conditioning with melphalan and fludarabine. Bone Marrow Transplantation (2001) 28, 101-103. Keywords: emlphalan; fludarabine; BMT; cardiotoxity The alkylating agent melphalan, either alone or in combination with other agents such as busulphan and total body irradiation, has been widely used in myeloablative conditioning regimens prior to stem cell transplantation for diseases such as multiple myeloma, 1 non-Hodgkin lymphoma 2 and Hodgkin's disease. 3 The clinical utility of melphalan has recently been extended by the development of nonmyeloablative transplant regimens intended to exploit the graft-versus-tumour effect of allogeneic T cell chimerism whilst reducing the toxicities associated with myeloablative conditioning. 4 Non-myeloablative regimens have seen melphalan used in novel combinations with agents such as the purine analogue, fludarabine. 5 The application of these novel regimens is particularly attractive in patients considered too old for standard allografts.It is conceivable that these regimens may lead to unexpected toxicities due to the cumulative or synergistic effects of the individual drugs, particularly in an older patient population. Although cardiac dysfunction is well described with other alkylating agents such as cyclophosphamide, 6 single-agent melphalan has not been shown to affect cardiac contractility in prospective studies. also only been rarely associated with cardiac dysfunction, with a single report of non-fatal congestive heart failure in two of 27 patients treated for chronic lymphocytic leukaemia. 8 Conditioning regimens combining fludarabine and melphalan have been associated with veno-occlusive disease and mucosal toxicity, but development of cardiotoxicity had not been specifically assessed in earlier reports. 5,9 Recently, in an updated series, reduced-intensity conditioning with melphalan and purine analogues was associated with the development of Bearman grade 3-4 cardiotoxicity in four of 86 patients. 10 The clinical features of cardiotoxicity in this setting have not, however, been documented. We describe the development of severe left ventricular failure (LVF) in three of 21 patients undergoing non-myeloablative stem cell transplantation (NMSCT) following conditioning with these agents. Case reportsTwenty-one patients have undergone NMSCT following conditioning with melphalan and fludarabine at our institution for multiple myeloma (11), chronic lymphocytic leukaemia (3), chronic myeloid leukaemia (2),...

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Summary:Bone marrow transplantation is potentially curative therapy for the hematologic complications associated with Shwachman-Diamond syndrome (SDS). This syndrome is, however, also associated with significant pancreatic and hepatic dysfunction, which may complicate BMT. We report a case of liver failure due to nonalcoholic steatohepatitis (NASH) following BMT for SDS. This case illustrates the need for assessing liver dysfunction pre-BMT in these patients, in addition to highlighting the potential risk posed by pre-existing steatosis for the development of rapidly progressive hepatic failure following transplantation. Bone Marrow Transplantation (2002) 29, 931-933.

Purpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-tageting antibodies. Whilst compelling preclinical data has highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib in CRC, this therapeutic strategy has not been investigated in clinical studies. Experimental Design: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with BRAF V600E positive metastatic colorectal cancer(mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960mg/twice-daily with erlotinib 150mg/daily selected as the recommended Phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% (10/31, 16% (5/31) confirmed) and 43% (3/7) respectively; with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS and MAP2K1 mutations, and MET amplification. Conclusions: The EVICT study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in undertsnidng potential mechanisms of resistance.