Stanley M. Marks

Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia

PURPOSE Chemoimmunotherapy combining fludarabine, cyclophosphamide, and rituximab (FCR) is an active regimen for untreated patients with chronic lymphocytic leukemia (CLL) with 70% complete responses (CRs) and 95% overall responses (ORs). However, grade 3/4 neutropenia was reported in 52% of cycles of treatment. The purpose of this trial was to maintain the high responses but reduce the toxicity of FCR by decreasing the fludarabine and cyclophosphamide (FCR-Lite). PATIENTS AND METHODS We conducted a single arm study of FCR-Lite which includes maintenance rituximab in 50 untreated CLL patients. Patients were evaluated for response using both the 1996 National Cancer Institute Working Group (NCIWG) guidelines and the 2008 guidelines. Two thirds of patients were treated by community physicians. RESULTS The median age was 58 years (range, 36 to 85 years); 20 patients had Rai stage 1, 22 had Rai stage 2, and eight had Rai stage 3 and 4. The OR and CR rates were 100% and 79%, respectively, using the 1996 NCIWG guidelines and 100% and 77% using the 2008 guidelines. Median duration of complete response was 22.3 months (range, 5.2 to 42.5 months) and none of the complete responders have relapsed. Grade 3/4 neutropenia was noted in 13% of the cycles of therapy. CONCLUSION FCR-Lite is highly effective in previously untreated CLL patients. Grade 3/4 neutropenia was dramatically reduced compared to standard FCR and our data demonstrated FCR-Lite can be safely administered in the community setting.

Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia.

To the editor: Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) is currently considered the gold standard first-line therapy for chronic lymphocytic leukemia (CLL).[1][1] In an attempt to reduce the neutropenia and maintain the high response rate of standard-dose FCR

Myasthenia triggered by immune checkpoint inhibitors: New case and literature review

Immune checkpoint molecules are potent regulators of immunologic homeostasis that prevent the development of autoimmunity while maintaining self-tolerance. Inhibitors of immune checkpoint molecules are used as immunotherapy in the treatment of melanoma and different types of refractory cancer, and can trigger various autoimmune complications including myositis and myasthenia gravis. We describe a case of generalized myasthenia gravis induced by pembrolizumab and review 11 other cases. Five patients also had elevated serum CK levels ranging from 1200 to 8729 IU/L, and biopsy showed myositis in one. Severity was highly variable as symptoms normalized spontaneously in one patient, but three others developed myasthenic crisis (including two with fatal outcomes). Steroids have been recommended as a preferred treatment of autoimmune complications of immune-checkpoint inhibitors. Myasthenia gravis should be considered when weakness, diplopia or bulbar symptoms are seen after treatment with immune checkpoint inhibitors, and additional studies are needed to characterize association with hyperCKemia.

Differentiation of immunostimulatory stem-cell- and monocyte-derived dendritic cells involves maturation of intracellular compartments responsible for antigen presentation and secretion

Dendritic cells (DCs) are important for the induction of primary T‐cell responses and may serve as “biologic adjuvants” in therapeutic protocols. However, given the “plasticity” of this antigen‐presenting cell, it remains unclear which DC type (source, subtype, and stage of differentiation) should be applied clinically. To provide additional insight in this selection process, we have, for the first time, analyzed the in vitro differentiation of CD34+ precursor‐derived and monocyte‐derived DCs for ultrastructure, phenotype, and function. The ultrastructural intracytoplasmic differentiation of DCs correlated with increasing T‐cell stimulatory activity of these cells. “Early‐stage”‐DCs proliferate, exhibit high levels of soluble antigen uptake, and moderate T‐cell stimulatory capacity, and are characterized by centrally located nuclei and numerous enlarged mitochondria. “Intermediate‐stage”‐DCs are enlarged cells with enhanced T‐cell stimulatory activity and pronounced cytoplasmic protein synthesis machinery. “Late‐stage” (LS)‐DCs exhibit a mature secretory cell phenotype and low proliferative index. They express high levels of the HLA‐DR, CD40L, B7‐1, and B7‐2 molecules and CD83, a specific marker of mature DCs, and appear maximally stimulatory to T cells. Ultrastructurally, LS‐DCs feature an accentric nucleus, an enlarged cytoplasm, containing numerous secretory storage vesicles, along with a fully developed Golgi complex. LS‐DCs exhibited numerous multivesicular and multilaminar structures containing major histocompatibility complex class II molecules, consistent with the MIIC (peptide‐loading) compartment. In extended studies, cultured CD14+ monocyte‐derived DCs displayed a similar, but accelerated, temporal differentiation staging pattern.

The impact of the omission or inadequate dosing of radiotherapy in extranodal natural killer T-cell lymphoma, nasal type, in the United States: Treatment Selection for NK T-Cell Lymphoma

Extranodal natural killer T‐cell lymphoma, nasal‐type (NKTCL), is a rare malignancy in Western populations and is thus challenging for standardization of care and a prospective study. This study was aimed at defining patterns of care for NKTCL in the context of radiotherapy (RT) use and dose selection in the United States.

IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant.

IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant

Langerhans cell histiocytosis and Erdheim-Chester disease, both with cutaneous presentations, and papillary thyroid carcinoma all harboring the BRAF(V600E) mutation.

Langerhans cell histocytosis (LCH) and Erdheim‐Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38‐year‐old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non‐LCH xanthogranuloma type lesion. BRAFV600E mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim‐Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAFV600E mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAFV600E mutation in a non‐LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim‐Chester disease workup. This is a unique case of a woman with BRAFV600E mutation positive Erdheim‐Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAFV600E mutation positive papillary thyroid carcinoma.

Peri‐transplant Clostridium difficile infections in patients undergoing allogeneic hematopoietic progenitor cell transplant

Clostridium difficile infections (CDI) remain the leading cause of infectious diarrhea among hospitalized patients in this country. Patients with hematologic malignancies, especially those who undergo hematopoietic progenitor cell transplants are particularly at risk for developing CDI. One hundred and forty seven consecutive allogeneic hematopoietic progenitor cell transplants were analyzed for peri‐transplant Clostridium difficile infections (PT‐CDI). Sixteen patients (11%) developed PT‐CDI (Median time = 7 days after transplant). The probability for developing PT‐CDI during the peri‐transplant period was 12.3%. History of CDI was strongly associated with the development of PT‐CDI (P = 0.008) (OR = 5.48) (P = 0.017). These patients also developed PT‐CDI much earlier than in those without a history (median 1 day vs. 8 days, P = 0.03). The probability for developing PT‐CDI for those with a history was 39%. There was a trend toward significance (P = 0.065) between matched related donor grafts and the development of PT‐CDI (OR = 0.245) (P = 0.08). Age, sex, diagnosis, transplant preparative regimens, Graft‐versus‐host disease (GVHD) prophylaxis, grade 3/4 acute GVHD, or use of antimicrobials within 8 weeks of transplant were not associated with PT‐CDI. Non‐CDI‐related deaths occurred in one patient in the PT‐CDI group and nine in the group without PT‐CDI. In the remaining 139 patients, the length of hospital stay for those with PT‐CDI was significantly longer than those without (mean 27 days vs. 22 days; P = 0.02). Am. J. Hematol. 91:291–294, 2016.

Inferior outcome after allogeneic transplant in first remission in high-risk AML patients who required more than two cycles of induction therapy.

While some patients with high‐risk acute myeloid leukemia (AML) require one or two cycles of induction chemotherapy to achieve a complete remission (CR), others require more than two cycles. We examined the outcomes of patients with high‐risk AML who received allogeneic HPC transplant in CR1. Forty five consecutive high‐risk AML patients in CR1 were included. All 45 patients had adverse cytogenetics, FLT 3 mutations, or secondary AML. Group A patients (n = 33) received one or two cycles, and Group B (n = 12) three or more cycles of induction chemotherapy. The patients were comparable in age, sex, white cell count at presentation, and time from diagnosis and from last chemotherapy to transplant. The 100‐day mortality rate was higher in Group B patients (50% vs. 9%, P = 0.006). They had a higher non‐relapse mortality (33% vs. 6%, P = 0.035) and a longer length of hospital stay from the day of stem cell infusion (median 21 vs. 20, P = 0.02; third quartile 22 vs. 28, P = 0.02). There was also a trend toward inferior event‐free survival and overall survival. High‐risk AML patients undergoing allogeneic transplant in CR1 after three or more cycles of induction chemotherapy have an inferior outcome and higher mortality when compared to those who only needed one or two cycles of induction chemotherapy. Novel strategies are needed to reduce the transplant‐related mortality in high‐risk AML patients needing more than two cycles of induction chemotherapy prior to allogeneic transplant in CR1. Am. J. Hematol. 90:715–718, 2015.

ICU intervention during induction chemotherapy for adult patients with newly diagnosed acute myeloid leukemia

We carried out a retrospective study on newly diagnosed AML patients to identify the risk factors associated with intensive care unit (ICU) intervention. One hundred and twenty consecutive AML patients were included. The median cycle of induction therapy (IT) was 2 (range 1-4). Ten patients (8%) needed ICU intervention during IT. The median time from first IT to ICU transfer was 16days (range 2-88days). Three patients required vasopressor/s, three mechanical ventilation, and four both. The cumulative probability for ICU intervention rose progressively with increasing cycles of IT received, from 2.5% during first induction to 27.5% at fourth induction. Age, sex, presentation white cell counts and coagulation profiles, cytogenetics, pre-chemotherapy ventricular ejection fractions, and prior chemoradiation were not risk factors. Univariate analysis identified a history of inflammatory bowel disease (IBD) (p=0.004) (RR=5.7; p=0.03) and positive blood cultures (BC) (p=0.03) (RR=3; p=0.06) as significant risks. Multivariate analysis found a history of IBD as the only significant factor (p=0.03), while positive BC (p=0.1) trending towards significance. AML patients with a history of IBD and positive BC are at increased risks for ICU intervention during IT.