Usama Gergis

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors

The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation.

Effectiveness and Safety of Tocilizumab, an Anti–Interleukin-6 Receptor Monoclonal Antibody, in a Patient With Refractory GI Graft-Versus-Host Disease

A 22-year-old white man with idiopathic, severe aplastic anemia underwent an allogeneic stem-cell transplantation from a human leukocyte antigen–matched sibling on June 4, 2008. Pretransplantation course was complicated by Klebsiella bacteremia and Clostridium difficile infection. The conditioning regimen consisted of cyclophosphamide 200 mg/kg and horse antithymocyte globulin 9 mg/kg and graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate 5 mg/m on days 1, 3, 6, and 11. On day 12, 1 day before engraftment, he developed stage 3 acute cutaneous GVHD. The skin rash completely resolved after starting prednisone 1 mg/kg. On day 32, he developed abdominal pain, nausea, vomiting, and watery diarrhea with a volume of 5 to 6 L per day and a recurrence of the maculopapular skin rash. He was treated with methylprednisolon 2 mg/kg and denileukin diftitox 4.5 mg/kg on days 1 to 5 and 8 and was enrolled onto a clinical trial for acute GVHD with mesenchymal stem cells versus placebo. A duodenal biopsy was consistent with GVHD. Abdominal cramping and diarrhea volume did not improve, and he then received additional immunosuppressive agents, including infliximab 10 mg/kg two times per week then once per week for four more doses and mycophenalate mofitil 1,000 mg two times per day, sirolimus 4 mg once daily, budesonide 3 mg two times per day, and photophoresis two times per week. By day 96, the patient was producing 600 mL of stool per day and being treated with methyprednisolone 50 mg once daily; budesonide, tacrolimus, and sirolimus; inflixamab once per week; and photophoresis twice per week. He had a GVHD Activity Index of 74, which correlates with a probability of mortality of 75% at day 200. During this period, an exhaustive effort was made to rule out other causes of diarrhea, such as cytomegalovirus (CMV), noravirus, cryptosporidial, mycobacterial, and fungal infections as well as mycophenalate toxicity. Diarrhea and cramping were relatively controlled, and prednisone was slowly tapered to 30 mg once per day; tacrolimus, budesonide, and sirolimus continued to be administered. However, on day 222, the patient experienced progressive abdominal pain and diarrhea with an increase in volume to 12 L per day. Colonic biopsies were consistent with GVHD without evidence of an infectious etiology. Again, he was treated with a series of immunosuppressive agents, including rabbit thymoglobulin 3 mg/kg, dacluzimab 5 mg/kg, and photopheresis and methotrexate 10 mg once per week. Diarrhea continued at a volume of 4 to 5 L a day. On day 295, repeat duodenal biopsies demonstrated preservation of villous architecture with mild regenerative changes in the deep crypt region (Fig 1A) and numerous apoptotic epithelial cells in the deep crypts (Fig 1B, black arrows). The colonic mucosal biopsy samples showed crypt architectural distortion in the absence of increased inflammation and apoptotic epithelial cells scattered throughout the crypts; some had the exploding appearance typical of GVHD (Figs 1C, 1D [black arrows]). As a result of the intense immune suppression, he experienced CMV and Epstein-Barr virus (EBV) reactivation and proven pulmonary Aspergillosis, and he became narcotic dependent. Because of the refractoriness of the patient to all known treatments for GVHD, we requested tocilizimab (TCZ) for compassionate use after carefully considering the rare but serious adverse effects of lower GI perforation and viral reactivation that have been reported in clinical trials. Institutional review board approval and informed consent were obtained. On the basis of a regimen that had been studied in patients with Crohn’s disease, we administered TCZ 8 mg/kg every 2 weeks for eight infusions beginning on day 413. After the first infusion, the patient reported a subjective improvement in abdominal cramping, diarrhea volume, and frequency. He continued to improve after each infusion (Fig 2, course of diarrhea in response to treatment for GVHD; black arrows, the first and last dose of toclizumab; MMF, mycophenolate mofetil; MTX, methotrexate; ATG, antithymocyte globulin). In addition, he stopped requiring intravenous hydration (2 L of normal saline daily before TCZ), parenteral electrolyte supplements, as well as platelet and red cell transfusion support. CMV and EBV polymerase chain reactions remained undetectable, and pulmonary aspergillosis was resolved with oral voriconazole 200 mg two times per day. On day 499, a repeat colonic biopsy was performed, which revealed reversion of the crypt architecture to near normal and rare shrunken apoptotic epithelial cells in the colonic crypts (Figs 1E, 1F [black arrow]). The patient received his last dose of TCZ on November 5, 2009. On November 20, 2009, he presented with a complaint of nausea and vomiting for 1 day. A computed tomography scan of the abdomen was interpreted as pneumoperitoneum and pneumoretroperitoneum around the colon and duodenum suspicious for a bowel perforation. A laparoscopic exploration did not find gas in the peritoneum or peritonitis or any other evidence of perforation. He improved spontaneously in a few days, and this episode was thought to be an ileus induced by narcotic dependence, which had occurred multiple times during his extensive course of treatment. The patient continued to be free of diarrhea and abdominal cramps 8 months after the completion of one course of TCZ and was undergoing immunosuppressive maintenance with prednisone 20 mg once per day and oral mycophenolate mofetil. Furthermore, his narcotic requirements decreased by 75% of the baseline before TCZ treatment. Patients with acute GVHD unresponsive to initial treatment with high-dose glucocorticosteroids have a 40% overall response rate to second-line immunomodulatory agents. Published response rates to acute GVHD therapy with tertiary therapies are in the range of 35%, and survival rates are approximately 10% at 1 year. Preclinical studies have implicated interleukin (IL) -6 as a key mediator of the inflammation responsible for the development of GVHD. TCZ is a humanized anti–IL-6 receptor monoclonal antibody that blocks IL-6 receptor signaling and trans-signaling; it has shown remission-inducing efficacy with a well-characterized safety profile in JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y VOLUME 28 NUMBER 30 OCTOBER 2

Voriconazole provides effective prophylaxis for invasive fungal infection in patients receiving glucocorticoid therapy for GVHD.

Patients on systemic glucocorticoids for GVHD after hematopoietic cell transplant are susceptible to invasive fungal infections (IFI), which greatly contribute to morbidity and mortality. We evaluated the efficacy of prophylactic treatment options (voriconazole or fluconazole vs itraconazole) for IFI by performing a retrospective review of patients on glucocorticoids for GVHD who were administered voriconazole (n=97), fluconazole (n=36) or itraconazole (n=36). IFI developed in 7/72 (10%) patients on fluconazole/itraconazole vs 2/97 (2%) on voriconazole (P=0.03) within the first 100 days of glucocorticoids. Five (7%) patients developed Aspergillus IFI on fluconazole/itraconazole, compared with none on voriconazole (0%) (P=0.008); Aspergillus IFI resulted in death in all five patients. We found that IFI occurred in patients who received an initial dose of at least 2 mg/kg/day of prednisone or equivalent; when the analysis was restricted to these patients, the hazard ratio (0.39; 95% confidence interval: 0.08–1.86) was consistent with a protective effect of voriconazole compared with fluconazole/itraconazole, although this subset analysis did not reach significance. OS at 100 days after start of glucocorticoids was 77% in patients administered fluconazole/itraconazole and 85% in those administered voriconazole (P=0.22). Our results suggest that voriconazole is more effective than fluconazole/itraconazole in preventing IFI, especially aspergillosis, in patients receiving glucocorticoids post transplant.

Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission

For adults with Philadelphia chromosome‐negative (Ph−) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric‐inspired chemotherapy may also offer durable leukemia‐free survival in the absence of HCT. We compared 422 HCT recipients aged 18–50 years with Ph‐ALL in CR1 reported to the CIBMTR with an age‐matched concurrent cohort of 108 Ph− ALL CR1 patients who received a Dana‐Farber Consortium pediatric‐inspired non‐HCT regimen. At 4 years of follow‐up, incidence of relapse after HCT was 24% (95% CI 19–28) versus 23% (95% CI 15–32) for the non‐HCT (chemo) cohort (P=0.97). Treatment‐related mortality (TRM) was higher in the HCT cohort [HCT 37% (95% CI 31–42) versus chemo 6% (95% CI 3–12), P<0.0001]. DFS in the HCT cohort was 40% (95% CI 35–45) versus 71% (95% CI 60–79) for chemo, P<0.0001. Similarly, OS favored chemo [HCT 45% (95% CI 40–50)] versus chemo 73% [(95% CI 63–81), P<0.0001]. In multivariable analysis, the sole factor predictive of shorter OS was the administration of HCT [hazard ratio 3.12 (1.99–4.90), P<0.0001]. For younger adults with Ph− ALL, pediatric‐inspired chemotherapy had lower TRM, no increase in relapse, and superior overall survival compared to HCT. Am. J. Hematol. 91:322–329, 2016.

Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

Impact of Prophylactic Levofloxacin on Rates of Bloodstream Infection and Fever in Neutropenic Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Few studies have evaluated the role of antibacterial prophylaxis during neutropenia in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (HSCT). At our center, levofloxacin prophylaxis was initiated in June 2006 in patients with myeloma who were undergoing autologous HSCT. We compared the incidence of bloodstream infection (BSI) and fever and neutropenia (FN) within 30 days of transplantation before (January 2003 to May 2006) and after (June 2006 to April 2010) the initiation of levofloxacin prophylaxis in patients undergoing autologous HSCT for myeloma. We also compared rates of BSI and FN during the same time periods in autologous HSCT recipients with lymphoma who did not receive antibacterial prophylaxis during either time period. After the initiation of levofloxacin prophylaxis, the BSI rate decreased from 41.2% (49 of 119) to 14.7% (23 of 156) and the rate of FN decreased from 91.6% to 60.9% in patients with myeloma (P < .001, for each). In contrast, rates of BSI (43.1% versus 47.3%; P = .50) and FN (98.8% versus 97.1%; P = .63) did not change in patients with lymphoma. Levofloxacin prophylaxis was independently associated with decreased odds of BSI (odds ratio, .27; 95% confidence interval, .14 to .51; P < .001) and FN (odds ratio, .18; 95% confidence interval, .09 to .36; P < .001) in multivariate analysis. Patients with myeloma had a nonsignificant increase in the risk of BSI due to levofloxacin-resistant Enterobacteriaceae (5% versus 1%, P = .08) and Clostridium difficile infection (7% versus 3%, P = .12) after the initiation of levofloxacin prophylaxis but did not have higher rates of BSI due to other resistant bacteria. Levofloxacin prophylaxis is associated with decreased risk of BSI and FN in patients with myeloma undergoing autologous HSCT.

Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival

Umbilical cord blood stem cell transplants are commonly used in adults lacking HLA-identical donors. Delays in hematopoietic recovery contribute to mortality and morbidity. To hasten recovery, we used co-infusion of progenitor cells from a partially matched related donor and from an umbilical cord blood graft (haplo-cord transplant). Here we compared the outcomes of haplo-cord and double-cord transplants. A total of 97 adults underwent reduced intensity conditioning followed by haplo-cord transplant and 193 patients received reduced intensity conditioning followed by double umbilical cord blood transplantation. Patients in the haplo-cord group were more often from minority groups and had more advanced malignancy. Haplo-cord recipients received fludarabine-melphalan-anti-thymocyte globulin. Double umbilical cord blood recipients received fludarabine-cyclophosphamide and low-dose total body irradiation. In a multivariate analysis, haplo-cord had faster neutrophil (HR=1.42, P=0.007) and platelet (HR=2.54, P<0.0001) recovery, lower risk of grade II–IV acute graft-versus-host disease (HR=0.26, P<0.0001) and chronic graft-versus-host disease (HR=0.06, P<0.0001). Haplo-cord was associated with decreased risk of relapse (HR 0.48, P=0.001). Graft-versus-host disease-free, relapse-free survival was superior with haplo-cord (HR 0.63, P=0.002) but not overall survival (HR=0.97, P=0.85). Haplo-cord transplantation using fludarabine-melphalan-thymoglobulin conditioning hastens hematopoietic recovery with a lower risk of relapse relative to double umbilical cord blood transplantation using the commonly used fludarabine-cyclophosphamide-low-dose total body irradiation conditioning. Graft-versus-host disease-free and relapse-free survival is significantly improved. Haplo-cord is a readily available graft source that improves outcomes and access to transplant for those lacking HLA-matched donors. Trials registered at clinicaltrials.gov identifiers 00943800 and 01810588.

Myelodysplastic syndromes: toward a risk-adapted treatment approach

Several classification and scoring systems have been developed in myelodysplastic syndromes (MDS to predict the risk of progression to acute myeloid leukemia and survival. These prognostication models have been also used to inform therapeutic decision-making in a risk-adapted fashion. Patient-related factors such as age, comorbidities, and functional status have to be considered as well. Here we review a risk-guided therapeutic approach for the management of MDS patients. It is anticipated that the improved understanding of the complex pathogenesis of MDS and the recent discovery of important molecular lesions will be translated into novel therapeutic approaches. Additionally, some prognostic aberrations are expected to be incorporated into the prognostic tools with the goal of improving their prognostic precision and therefore allow for a more informed therapeutic decision-making based on the individual’s risk profile.

Management of Refractory Acute Myeloid Leukemia: Re-induction Therapy or Straight to Transplantation?

Patients with primary resistant and relapsed acute myeloid leukemia (AML) are rarely cured without undergoing allogeneic stem cell transplantation. What is currently debated is whether a trial of re-induction chemotherapy prior to transplantation is beneficial. Data from multiple retrospective analyses have shown that pretreatment variables are useful in predicting response to salvage chemotherapy. For patients unlikely to respond, re-induction attempts may be detrimental, leading to added organ toxicity and possible increased tumor resistance. Allogeneic transplantation in the setting of active disease is the alternative strategy. Multiple studies have demonstrated the feasibility of this approach, but cure rates have been low with the use of traditional transplant approaches. Newer strategies employing allogeneic transplantation earlier in patients with relapsed or refractory AML, as well as the incorporation of novel and effective antileukemic agents into the transplant conditioning regimen, may lead to better outcomes.

Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation

To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post‐transplantation.