Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma.

BACKGROUND: More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma. MATERIALS AND METHODS: We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations. RESULTS: In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy. CONCLUSIONS: This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and alkeran in multiple myeloma autologous transplantation.

Propylene Glycol-Free melphalan HCL for Injection (PGF-Mel) is a new formulation that incorporates Captisol, a specially modified cyclodextrin, to improve melphalan stability. In this phase IIa, open-label, randomized, cross-over design bioequivalence study, the pharmacokinetics of PGF-Mel were compared with the marketed formulation of melphalan, or Alkeran. Patients received half of the total dose of melphalan in the form of Alkeran and the other half in the form of PGF-Mel in an alternating manner. The pharmacokinetic measures were determined using WinNonlin 6.2 and bioequivalence was assessed using log-transformed systemic exposure parameters. Twenty-four patients, 11 females and 13 males, were enrolled between 4 February 2010 and 16 May 2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. The median age of enrolled subjects was 58 years (range: 48-65). All patients achieved myeloablation 3 days post autologous graft followed by successful neutrophil engraftment with a median of 11 days after transplant. Pharmacokinetic analysis showed that PGF-Mel was bioequivalent with Alkeran and also revealed that maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were higher (~10%) after PGF-Mel administration. In conclusion, PGF-Mel is considered bioequivalent to Alkeran while also demonstrating a marginally higher systemic drug exposure.

Intestinal ischemia after allogeneic stem cell transplantation: a report of four cases.

Gastrointestinal ischemia after allogeneic bone marrow transplantation is a rare complication not well-described in the literature. Herein we retrospectively review charts of four patients who developed intestinal ischemia after allogeneic bone marrow transplantation at our institution. The patients were found to be predominately younger males who presented with nonspecific abdominal pain. Graft-versus-host disease was a common finding among all patients. Laboratory values suggestive of microangiopathy were present in two patients. Obesity and hypertriglyceridemia were cardiovascular risk factors found in these patients. The development of thrombotic microangiopathy and cardiovascular risk factors after allogeneic bone marrow transplantation may predispose patients to gastrointestinal ischemia and may portend a poor prognosis.

Promising cellular therapeutics for prevention or management of graft-versus-host disease (a review).

Graft-versus-host disease (GVHD) frequently occurs following allogeneic hematopoietic stem cell transplantation. The primary treatment for GVHD involves immune suppression by glucocorticoids. If patients become refractory to steroids, they have a poor prognosis. Therefore, there is a pressing need for alternative therapies to treat GVHD. Here, we review clinical data which demonstrate that a cellular therapy using mesenchymal stromal cells (MSCs) is safe and effective for GVHD. Since MSCs derived from bone marrow present certain limitations (such as time lag for expansion to clinical dose, expansion failure in vitro, painful and invasive bone marrow MSC isolation procedures), alternative sources of MSCs for cellular therapy are being sought. Here, we review data which support the notion that MSCs derived from Wharton's jelly (WJ) may be a safe and effective cellular therapy for GVHD. Many laboratories have investigated the immune properties of these discarded MSCs with an eye towards their potential use in cellular therapy. We also review data which support the notion that the licensing of MSCs (meaning the activation of MSCs by prior exposure to cytokines such as interferon-γ) may enhance their effectiveness for treatment of GVHD. In conclusion, WJCs can be collected safely and painlessly from individuals at birth, similar to the collection of cord blood, and stored cryogenically for later clinical use. Therefore, WJCs should be tested as a second generation, off-the-shelf cell therapy for the prevention or treatment of immune disorders such as GVHD.

Late-onset intestinal perforation in the setting of posttransplantation microangiopathy: a case report.

Intestinal perforation in the setting of posttransplantation microangiopathy (TMA) is a very rare event and might be considered a terminal event of intestinal microangiopathy (i-TMA), a rather rarely recognized posttransplantation complication, as it overlaps with the more common intestinal graft-versus-host disease (GVHD). Cases of i-TMA described in literature occurred within with first 100 days posttransplantation or shortly thereafter. In this report, we describe a case of late-onset intestinal perforation that occurred in the setting of systemic microangiopathy more than a year after allogeneic transplantation. In our case, the patient poorly responded to treatment secondary to refractory mircoangiopathy.

Blastic plasmacytoid dendritic cell neoplasm should be treated with acute leukemia type induction chemotherapy and allogeneic stem cell transplantation in first remission.

Blastic plasmacytoid dendritic cell (BPDC) neoplasm is a rare but clinically aggressive tumor known to be derived from the precursors of plasmacytoid dendritic cells (CD123+) with a high frequency of cutaneous and bone marrow involvement. Though majority of the patients initially respond to multi-agent chemotherapy, most would relapse within a year. We hereby report a patient with disseminated cutaneous BPDC with marrow involvement diagnosed by typical histo-pathological and flow-cytometric findings. He was subsequently treated with leukemia type induction regimen followed by allogeneic stem cell transplantation in first complete remission. He is now 18 months posttransplantation with continued remission with full donor chimerism. We recognize that BPDC with marrow involvement behaves like acute myeloid leukemia and aggressive treatment followed by stem cell transplantation may lead to long-term remission in selected cases.

Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach.

BK virus (BKV) reactivation occurs in 50% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Standardized antiviral management of BKV infection has not been established. In order to develop a uniform guideline, a treatment algorithm for the management of symptomatic BKV replication was implemented for our allo-HSCT population. This is a retrospective analysis of patients treated according to the protocol between January 2008 and January 2009. Eighteen patients developed symptomatic BKV replication a median of 43 days after allo-HSCT. All patients had BK viruria and 12 patients had BK viremia in addition to viruria. Patients with isolated viruria were treated with intravenous (IV) low-dose cidofovir (0.5-1mg/kg IV weekly) until symptom resolution. In patients with BK viremia, therapy was continued until virological clearance was achieved in the blood. Four patients also received intravesical instillation of cidofovir per physician discretion. Thirteen of 18 (72%) patients with viruria and 8 of 12 (75%) patients with viremia responded to treatment. Three patients developed transient renal dysfunction. Low-dose cidofovir is safe and effective in allo-HSCT recipients. In absence of randomized prospective data, an institutional algorithmic protocol removes variance in practice pattern and derives data that may be used for research and improved patient care.

Use of rituximab and irradiated donor-derived lymphocytes to control Epstein-Barr virus-associated lymphoproliferation in patients undergoing related haplo-identical stem cell transplantation.

Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) is an uncommon but potentially fatal complication of allogeneic stem cell transplantation. We report here two patients who underwent T cell-depleted mismatched-related stem cell transplantation for hematologic malignancies and required aggressive post-transplant immunosuppression for graft-versus host disease (GVHD). Both patients subsequently developed markedly elevated EBV-DNA titers in association with monoclonal, light chain-restricted B cell populations in the blood. Although immunosuppressive medications were rapidly tapered, neither patient could receive potentially curative therapy with unmanipulated donor-derived lymphocyte infusions (DLI) because of the substantial risk of severe GVHD. Therefore, both patients received repeated courses of rituximab, an anti-CD20 monoclonal antibody, in combination with irradiated DLI. This therapeutic strategy resulted in normalization of the elevated EBV-DNA titers and disappearance of the monoclonal B cell populations. Our results suggest that rituximab and possibly irradiated DLI played an important role in controlling early EBV-LPD in these two patients and may be an effective alternative therapeutic strategy for patients who develop EBV-LPD post transplant and are unable to receive unmanipulated DLI.

Late onset Epstein-Barr virus-associated lymphoproliferative disease after allogeneic bone marrow transplant presenting as breast masses.

We report a patient who developed breast masses 17 months after a T cell-depleted partially mismatched related donor (PMRD) bone marrow transplant (BMT) for chronic myeloid leukemia. The patient had severe chronic graft-versus-host disease (GVHD) and the masses were due to Epstein-Barr virus (EBV) lymphoproliferative disease (LPD). The patient expired from fungal pneumonia after chemotherapy for the EBV-LPD.

The effect of alloxan-induced diabetes on triamine lesions in the ventromedial hypothalamus.

It has been demonstrated that the ventromedial hypothalamus (VMH) of alloxan-induced diabetic mice is protected from subsequent gold thioglucose (GTG)-induced lesions. Another compound, 3,3'-methyliminobis-(N-methylpropylamine) (MIMPA), a triamine structurally unrelated to GTG, has been shown to cause similar VMH lesions in mice. We chose to investigate the effect of alloxan-induced diabetes on VMH lesion formation in MIMPA-treated mice. In this study CF-1 female mice were made diabetic by a simple intravenous (IV) injection of alloxan and subsequently treated with MIMPA by subcutaneous injection (SC). Contrary to studies which showed that GTG-induced VMH lesions are insulin dependent, an insulin deficiency did not inhibit MIMPA-induced lesions in the VMH of mice. Our data suggests, albeit GTG is suspected to induce VMH necrosis by attaching to glucoreceptors and insulin-sensitive neurons, MIMPA works by a different and as yet unknown mechanism. We conclude that MIMPA-induced lesions in the VMH of mice are not insulin dependent.

Beta-thioglucose inhibits gold thioglucose lesions in the ventromedial hypothalamus.

Gold thioglucose (GTG) has been known to be an obesity causing agent for over 40 years. GTG works by affecting dendrites in the mouse ventromedial hypothalamus (VMH) producing a permanent VMH lesion and subsequent hyperphagia and obesity. We have investigated the effect of beta-thioglucose (BTG), a glucose antimetabolite, on GTG-induced lesions in the VMH of mice. Twenty-eight female CF-1 mice were used in this study. Seven micron sections were made of the mouse VMH, mounted on glass slides, and stained with hematoxylin and eosin. A previous report of BTG action on GTG-induced lesions has not supported a competitive inhibition between these two drugs. Our data demonstrate that at 1/2 hour, 6 hours, and 12 hours post BTG, BTG completely inhibited GTG-induced lesions in the VMH.

Terminal cretaceous extinction scenario for a catastrophe.

All the biotic changes that occurred at the end of Cretaceous time, including the extinction of the dinosaurs, may be the result of a single terrestrial catastrophe. The Arctic spillover model, first proposed to explain the marine extinctions, would have caused a rapid and intense change in the earth's climate including a lowering of temperature and of precipitation. This change in climate may have triggered a series of ecological disasters that included the radical change in the distribution of vegetation on the earth as well as the extinction of the dinosaurs.

Planetary-scale forcing of the january 1977 weather.

The type of weather anomalies that occurred in the United States during January 1977 are typical of a planetary-scale wave phenomenon called stratospheric sudden warming (SSW). Specific changes in weather parameters nearly always accompany SSW. Blocking ridges (intensified high-pressure cells) develop over the oceans, the North Pole warms, mid-latitudes cool, and continental temperatures plunge. These characteristics usually persist for at least a month. When the SSW is strong, as in January 1958, 1963, and 1977, the accompanying weather anomalies can be unusually severe.