PEITC in End-Stage B-Cell Prolymphocytic Leukemia: Case Report of Possible Sensitization to Salvage R-CHOP
Perm J 2016 Spring;20(2):74-80
Introduction: B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive leukemia distinct from chronic lymphocytic leukemia, with median survival of only 3 years. B-PLL is resistant to most chemotherapy and newer targeted therapies such as alemtuzumab and thalidomide. Phenylethyl isothiocyanate (PEITC) is a natural compound from horseradish with evidence for therapeutic potential in multiple leukemia types.
B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive lymphoid leukemia with gene expression distinct from that of chronic lymphocytic leukemia.1 B-PLL is often refractory to chemotherapy, resulting in median survival of only three years.2 Reports have been published of improved response rates with intravenous alemtuzumab,2 partial remission with thalidomide,3 and cure with allogeneic peripheral stem-cell transplantation.4 In refractory patients, R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin hydrochloride], Oncovin [vincristine sulfate], Prednisone or Prednisolone) is sometimes used as salvage therapy but is seldom successful and prognosis remains poor, with little evidence supporting its clinical use.5
Phenylethyl isothiocyanate (PEITC) is a natural compound obtained from horseradish and watercress,6 with mechanistic and therapeutic evidence for multiple types of leukemia. The antileukemic effect is dose- and time-dependent, acting through multiple tumor suppression signaling pathways: inactivation of protein kinase B (PKB/Akt) and activation of c-Jun N-terminal kinase (JNK) pathways, caspase activation, poly [ADP-ribose] polymerase (PARP) cleavage/degradation, and promotion of apoptosis.7 PEITC is a biological response modifier, acting as a strong inflammation reducer.8 Notably, PEITC exhibits tumor cell inhibition properties in fludarabine-resistant chronic lymphocytic leukemia cells obtained from patients, by elevation of reactive oxygen species,9,10 and by promoting immune response (increasing monocyte macrophage phagocytosis, and increasing natural killer cell cytotoxic activity).11 A cytotoxic effect on chronic myeloid leukemia cells is achieved through induction of reactive oxygen species (ROS) stress and oxidative damage.10
Dietary chemopreventive effects have been identified for PEITC, which works through multiple signaling pathways, at typical human nutritional doses.12,13 PEITC is one of numerous dietary compounds that work at the epigenetic level: anacardic acid, curcumin, diallyldisulfide, dihydrocoumarin, diindolylmethane, folate, garcinol, genistein and soy isoflavones, indol-3-carbinol, lycopene, nordihydroguaiaretic acid, phenylhexyl isothiocyanate, polyphenols (present in green tea, apples, coffee, chocolate, and raspberries), resveratrol, retinoic acid, selenium, and sulforaphane or PEITC (both of which are from the cruciferous family of vegetables). Metabolic pathways influencing tumor initiation and promotion are also affected by PEITC, through inhibition in human glioma cells of hypoxia-induced HIF-1alpha accumulation and vascular endothelial growth factor expression.14
PEITC reverses platinum resistance in lung cancer by inhibiting glutathione-mediated drug efflux,15 in cisplatin-resistant gastric cancer by suppressing PI3K-PKB/Akt,16 and in Adriamycin-resistant bladder cancer by blocking PKB/Akt and activating mitogen-activated protein kinase (MAPK) pathways.17 Additionally, there is synergy of PEITC with chemotherapy drugs: with paclitaxel to enhance apoptosis in MCF-7 breast cancer,18 and with taxol in drug-resistant MCF7 and MDA-MB-231 breast cancer cells by growth inhibition, cell cycle arrest, and apoptosis.19 In Tables 1 and 2, we concisely summarize the evidence for PEITC: synergism with chemotherapy drugs, direct tumor inhibition, inhibition of metastases, reversal of chemoresistance, and chemoprevention.
However, PEITC has not been reported in mechanistic studies of B-PLL cells or treatment of B-PLL patients. The current case report documents possible pre-sensitization of the patient’s B-PLL cells to salvage therapy with R-CHOP, a treatment that typically has poor response in B-PLL patients. This report was prepared in accordance with the CARE (CAse REport) guidelines.20
Our patient was a 53-year-old man, who was in his usual state of health and good spirits until slow onset of fatigue, dyspnea on exertion, abdominal bloating, night sweats, joint pain, and a 15-lb weight loss from 180 lbs to 165 lbs (Figure 1). Chest radiograph found pneumonia, and palpation revealed no lymph node enlargement but marked splenomegaly. Hematology showed elevated white blood cells (WBC; 157.1 K/mL), low red blood cells (2.94 M/mL), polychromasia 1+, ovalocytes 1+, smudge cells 1+, CD20+ small B-cells with diffuse nodular infiltrate, and CD5+ cells (Figures 2-5; Table 3).
Planned frontline therapy was 6 cycles of fludarabine-cyclophosphamide-rituximab (FCR) chemotherapy (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2/d, and rituximab 125 mg/m2 intravenous) and supportive medication (Neupogen, Allopurinol, Bactrim DS, acyclovir, prochlorperazine, and dexamethasone). Disease progression occurred following 2 cycles of FCR, with fever, lower but still elevated WBC (110.7 K/mL), low red blood cells (3.74 M/mL), and increased anisocytosis (2+). On pathology review, the diagnosis was updated to B-PLL, stage IV, with Eastern Cooperative Oncology Group performance score of 2.
Five months after diagnosis of PLL, following 12 cycles of weekly alemtuzumab, there was stabilization of WBC (5.2 K/mL) and red blood cells (4.31 M/mL), but persistent polychromasia (1+) and ovalocytes (1+). Because the patient had 2 siblings, planning and evaluation for allogenic bone marrow transplant was initiated.
Ten months after diagnosis, the patient reported profound fatigue, blurred vision, pressure behind his eyes, spontaneous unprovoked perspiration, and abdominal distention with early satiety. Palpation revealed extensive splenomegaly across the midline to the right midclavicular line, confirmed by computed tomography (Figure 6). Three treatments of palliative radiation therapy were unsuccessful, therefore splenectomy was performed. Following surgery, the patient developed protein energy malnutrition, sinus tachycardia, bilateral pleural effusion, cholelithiasis, dyspnea, and portal vein thrombosis. For treatment of his significant pain, the patient was referred to the integrative pain management service for acupuncture (daily during this and following hospital admissions).
Eleven months after diagnosis, despite 2 cycles of alemtuzumab with palliative intent, there was further disease progression. The patient was readmitted for sepsis with fever, lactic acidosis (4.9 mmol/L), worsening serology, and atypical lymph at 92% (Table 1). Because of significant pleural effusion, the patient underwent transpleural thoracoscopy, exploratory thoracotomy, and lung decortication. Given the patient’s deteriorating status, bone marrow transplantation was canceled and a palliative care team was assigned to his case.
Adjunctive oral PEITC was introduced, with the patient being eligible on the basis of published evidence for disease-modifying potential, and lack of evidence for herb-drug interactions. PEITC was provided to the patient on a compassionate use basis because there were no treatment options left available to him. Two weeks after PEITC was initiated, the patient’s oncologist added pentostatin to his alemtuzumab, given the alemtuzumab’s poor potential for success.
PEITC was provided by KW Botanicals (San Anselmo, CA) as a 1:1 watercress fluid extract of the fresh leaf, prepared from cloned Nasturtium officinalis using corn alcohol, with plant identity verified by a botanist, using organoleptic methodology and microscopy. Daily oral dose of the extract was 2 mL, corresponding to an approximate daily dose of PEITC of 1 mg, for a duration of 3 weeks. Following introduction of PEITC, the patient’s symptoms continued to improve, but WBC remained abnormal.
Twelve months after diagnosis, there was continued disease progression, with a new left neck mass, night sweats, chills without fever, and elevation of WBC to 207.7 K/mL. Examination revealed a 5 cm, tender mass. Computed tomography showed extensive left cervical adenopathy. Treatment was changed to salvage R-CHOP (3 cycles, every 3 weeks), and PEITC discontinued one week before starting R-CHOP. The patient’s response to sequential 8 weeks of PEITC/pentostatin, followed by 6 cycles of R-CHOP, was substantial, with normalization of WBC within 2 days (from 150K/mL to 9.8 K/mL). R-CHOP was continued for 6 cycles, leading to discharge from the palliative care team.
Fifteen months after initial diagnosis, and following this course of sequential 8 weeks of PEITC/pentostatin and then 6 cycles of R-CHOP, the patient received allogenic peripheral blood stem cell transplant on an outpatient basis at Stanford University Hospital in Stanford, CA, and was followed up for 90 days after the transplant. Posttreatment bone marrow biopsy was normal; neck lesions and chest and left pelvic lymphadenopathy resolved, with only mild residual fluorodexyglucose (FDG) uptake. Other previously noted lesions in both lung bases appeared stable in size and FDG uptake. The patient was declared to be in remission.
Forty-three months after initial diagnosis, the patient’s remission continues. Other than one episode of neutropenic fever and chronic mild to moderate graft-versus-host disease, the patient remains well to this day, with no evidence of CD20+ small B-cells.
PEITC exhibits synergism with numerous chemotherapy drugs,18,21,22 including doxorubicin, which is a component of R-CHOP.23 We were not able to identify published evidence for synergism of PEITC with pentostatin. Researchers have also shown that PEITC has direct and significant oxidative cytotoxic activity against other leukemia cells—with low toxicity to normal lymphocytes—such as chronic lymphocytic leukemia cells obtained from patients whose disease was resistant to fludarabine chemotherapy.9 Cells from those patients were eliminated by PEITC.
At present, it is known that one way in which PEITC accomplishes this sensitization of cancer cells to chemotherapy is by depleting the cancer cells of tubulin, a normally stable cell structure protein required in the process of cell cycle progression.24 It has also been found that this degradation of tubulin by PEITC is an irreversible process,25 suggesting there is biological plausibility for our patient’s PLL tumor cells to continue to exhibit enhanced vulnerability for some time after PEITC exposure. Taken together, these data support our hypothesis that this patient’s chemoresistant B-PLL cells were sensitized to favorable response to R-CHOP, a drug not expected to have been so successful in his end-stage condition.5 This favorable response enabled him to requalify for life-saving allogenic peripheral blood stem cell transplant.
PEITC exhibits chemopreventive effects in the following cancer cell lines and animal models: breast,26,27 cholangiocarcinoma,28 colon,29,30 and oral (squamous).31 These effects are mediated via numerous pathways and mechanisms: anti-angiogenesis,26 induction of apoptosis,27,28,30 inhibition of EGFR, MMP-2 and MMP-9,31 modulation of carcinogen-metabolizing systems,32 and NF-kB suppression.33 In the animal model studies, these effects were seen at oral doses reflecting human dietary intake of PEITC-containing foods.26,32 PEITC additionally accomplishes direct tumor cell inhibition, in the following cell lines and animal models: brain (glioma),34,35 breast,36 cervical,37 leukemia,38,39 melanoma,40 and pancreatic.41,42 Two recent studies also suggest PEITC has metastatis inhibition capabilities in breast43 and prostate44 cancers (Table 1).
Promising chemotherapy-specific effects have been described for PEITC: reversal of chemoresistance data exist for bladder cancer and adriamycin,45 breast cancer and taxol,46 gastric cancer and multidrug resistance gene,47 lung cancer and cisplatin48 (Table 2). Synergism with specific chemotherapy agents in defined cancers has been reported for bortezomib49 and paclitaxel50 in breast cancer, and cisplatin in lung cancer.48
This case report provides justification of in vitro PEITC-drug synergy testing, which if successful would be a step toward in vivo and phase I combination therapy trials.
The author(s) have no conflicts of interest to disclose.
We thank Greg Rumore, MD, Chief of Staff, Pathology, Kaiser Permanente Walnut Creek Medical Center in Walnut Creek CA, for providing hematoxylin and eosin stain and immunohistochemical stain photographs.
Mary Corrado, ELS, provided editorial assistance.
1. Del Giudice I, Osuji N, Dexter T, et al. B-cell prolymphocytic leukemia and chronic lymphocytic leukemia have distinctive gene expression signatures. Leukemia 2009 Nov;23(11):2160-7. DOI: https://doi.org/10.1038/leu.2009.137.