Page 1298 - Hematology_ Basic Principles and Practice ( PDFDrive )

1144 Part VII Hematologic Malignancies

thrombocytopenia were frequent in the ruxolitinib arm (45.2% and Phase I/II data of momelotinib (CYT387, Gilead) in patients with
12.9%, respectively), discontinuation for these events was extremely MF is notable for the potential durable anemia response reported
rare. The primary endpoint in the COMFORT-2 trial was met at 48 (70% transfusion independence). Headache and elevated lipase levels
weeks, with 28% of patients in the ruxolitinib arm and 0% in the were determined to be the dose limiting toxicities of momelotinib
BAT arm achieving at least a 35% reduction in spleen volume. The treatment. Pacritinib (SB1518, CTI Biopharma) has been evaluated
mean length of palpable spleen decreased by 56% at 48 weeks in a phase I/II trial in which treatment-emergent myelosuppression
compared with an increase of 4% in the BAT arm. Sophisticated was limited and appears to be effective in safely reducing spleno-
disease-specific quality-of-life tools were used to evaluate the effects megaly in patients with low baseline platelet levels. The results of the
of ruxolitinib therapy on the systemic symptoms that have been phase III PERSIST-1 trial were recently presented and confirmed the
presumed to be a consequence of the increased elaboration of inflam- beneficial effects of this JAK2/FLT3 inhibitor in 327 ruxolitinib-
matory cytokines modulated by JAK1 signaling. The effects of rux- naïve, intermediate/high-risk MF patients with any baseline platelet
olitinib were, however, limited in that reversal of histomorphologic count. Compared with the best available therapy arms (excluding
abnormalities, including BM fibrosis or osteosclerosis, significant ruxolitinib), pacritinib was superior in achieving the primary end-
reduction in the JAK2V617F allele burden, and loss of marker point of spleen reduction (19.1% vs. 4.7%) without a significant
cytogenetic abnormalities indicating that the underlying malignant increase in hematologic toxicity. Gastrointestinal toxicity was more
potential of PMF is not affected by this therapy. In addition, abrupt frequently observed with pacritinib therapy (diarrhea 50%) but
discontinuation of ruxolitinib therapy was associated with rapid mostly grade 1/2 and not a frequent reason for drug discontinuation.
return to baseline levels of splenomegaly and severity of the systemic Additionally, RBC transfusion independence was achieved in 25% of
symptoms that at times can be disabling. More gradual tapering of transfusion-dependent patients at baseline. Fedratinib (SAR302503,
this agent or the use of a short steroid taper is recommended to avoid Sanofi Aventis) was a selective JAK2 inhibitor with positive results
this complication. Ruxolitinib is an important agent for the palliation reported in two phase III trials conducted in MF patients, but
of symptomatic splenomegaly and the debilitating symptoms seen in was unfortunately found to be associated with the emergence of
patients with PMF. The survival data from the COMFORT 1 trial, Wernicke encephalopathy in several patients. This drug is no longer
although modest, are intriguing and suggest that even if an appre- in clinical development and joins several other JAK2 inhibitors that
ciable impact on abnormal BM histopathology or molecular or are no longer being tested due to concerns regarding treatment-
cytogenetic responses is not seen with ruxolitinib, pharmacologic related toxicity such as XL019, AZD1480, and BMS-911543.
suppression of the JAK pathway decreases the risk of death, perhaps Splenic irradiation has frequently been used in the past for treat-
simply by improving the overall performance status, and reversing ment of the painful large-spleen syndrome, but is now considered a
cancer cachexia of an individual. The use of ruxolitinib has been last-resort option with the approval of JAK1/2 inhibitor therapy.
demonstrated to be safe is patients with a minimum platelet count Irradiation in fractions of 0.15–1 Gy administered daily or by an
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of 50 × 10 /L. The need to treat patients who are asymptomatic with intermittent fractionation schedule (i.e., two or three times a week)
limited splenomegaly is not apparent since treatment does not appear to a total dose per treatment course of 2.5–6.5 Gy may be effective.
to affect the underlying malignant disorder. With a median follow-up Responses are transient, lasting an average of 3.5 months, and hema-
of 3 years, the mature results of the COMFORT-1 trial demonstrate topoietic toxicity is frequently significant. Splenic irradiation is
a durable response in spleen reduction and symptom improvement especially useful for treatment of splenic pain of sudden onset and
in those subjects that remain on treatment. The absence of new/ for treatment of ascites caused by implants of hematopoietic tissue.
unexpected toxicities or late-onset emergent hematologic adverse Radiation therapy should be considered as a temporary measure to
events was also appreciated. However, it should be noted that a 50% be used in patients who are too ill to tolerate splenectomy or chemo-
discontinuation rate was reported in the arm originally randomized therapy. Splenic irradiation is limited by myelosuppression with sig-
to ruxolitnib, and the potential for leukemic transformation with sites nificant prolonged cytopenias, which is not predictable and is not
of extramedullary leukemia have also been reported. Patients treated correlated with the doses of radiation administered.
with ruxolitinib have been noted to have an increased incidence of Radiotherapy offers a viable treatment option and sometimes may
infectious complications, including toxoplasmosis, cryptoccocal be the therapy of choice for the treatment of patients with symptom-
pneumonia, reactivation of latent herpes simplex virus and hepatitis atic hepatomegaly, peritoneal and pleural implants or pulmonary
B, and disseminated tuberculosis. An almost threefold increase in the infiltration leading to ascites or pleural effusions, and EMH in vital
incidence of herpes zoster infections has been observed, suggesting organs leading to organ dysfunction. Because of the inherent sensitiv-
that the drug may promote clinically significant suppression of cell- ity of myeloid tissue to radiation and profound BM suppression that
mediated immunity. A profound and prolonged reduction in may occur after irradiation, therapy is usually initiated at low doses
T-regulatory and natural killer cells has been observed in patients (20–25 cGy/day), with modification of the dose as the clinical situ-
treated with ruxolitinib, which is likely a consequence of downregula- ation dictates. An alternative approach using intraperitoneal admin-
tion of inflammatory cytokine expression. The determination of how istration of cytosine arabinoside has been used to treat ascites in PMF.
prevalent these infectious complications are will require careful long- Low-dose, single-fraction, whole-lung radiotherapy has also been
term follow-up of large cohorts of patients being treated with this useful in treating pulmonary artery hypertension associated with
drug for prolonged periods of time. PMF.
A number of other small-molecule inhibitors of JAK2 are under Splenectomy remains a viable option even in the face of the recent
various phases of clinical development, and all appear to be generally availability of JAK2 inhibitors in patients with hemolysis, thrombo-
effective in reducing splenomegaly and improving symptom burden. cytopenia, painful splenomegaly, recurrent splenic infarction, and
It is important to note that none of the currently tested JAK2 inhibi- portal hypertension refractory to other therapeutic modalities or in
tors have been shown to clearly achieve complete BM pathologic individuals with leukopenia or thrombocytopenia that prevents one
responses or induce cytogenetic/molecular remissions. Additionally, from resorting to therapy with chemotherapeutic agents or a JAK2
data to support the superiority of one agent over another do not exist. inhibitor. Splenectomy in patients with PMF is associated with a
Momelotinib (JAK1/JAK2 inhibitor) and pacritinib (JAK2/FLT3 postoperative morbidity rate of 15–30% and a mortality rate of
inhibitor) are currently being evaluated in phase III registration trials, almost 10%. The appropriate implementation of splenectomy can
and have the potential to be used as either first-line agents in ruxoli- result in the improved quality of life of PMF patients who frequently
tinib-naïve patients with significant baseline cytopenias, or as second- do not have other therapeutic options available. Because splenectomy
line agents for patients experiencing ruxolitinib-associated cytopenias is associated with significant morbidity and mortality, the physician
or loss of clinical response. These agents have different target specifici- should only resort to this strategy if thrombocytopenia, anemia, or
ties and toxicity profiles, and require further evaluation in mature symptomatic splenomegaly is unresponsive to less invasive approaches
clinical trials to ultimately determine their utility in comparison to such as JAK2 inhibitor treatment. Progressive hepatomegaly and
ruxolitinib. marked thrombocytosis occurred, respectively, in 16% and 22% of