SEPTEMBER)2019

In this month’s Leukemia Insights newsletter, written by Prithviraj Bose, MD, and Srdan Verstovsek, PhD, MD, and sponsored in part by the Charif Souki Cancer Research ABOUT)MyMDAnderson Fund, we summarize the investigational approaches available for patients with myeloproliferative neoplasms (MPN) at MD Anderson Cancer Center. myMDAnderson is`a`secure,` personalized`web`site`helping` community`physicians`expedite`patient` referrals,`as`well`as`improve`continuity` Innovative)Treatment)Strategies)for) of`care`through`information`access` Classic)and)Atypical)Myeloproliferative) and`streamlined`communications.` Physicians`who`have`referred`patients` Neoplasms)(MPN) to`MD`Anderson`or`plan`to`do`so,`can` utilize`the`HIPAA`compliant`features In August 2019, the FDA approved the JAK2 inhibitor fedratinib for the of`myMDAnderson`to: treatment of patients with myelofibrosis (MF), only the second drug approval in the classic myeloproliferative neoplasm (MPN) space after • Refer`a`patient ruxolitinib was approved for MF in 2011 and polycythemia vera (PV) in • View`your`patient's`appointments` 2014. Hopefully, this is the first of many regulatory approvals as a Access`patient`reports number of investigational agents appear promising in recent and • Send`and`receive`secure` ongoing trials. Below, we summarize the investigational approaches messages available for patients with MPN at MD Anderson.

1.)Pemigatinib for)myeloid/lymphoid)neoplasms)with)FGFR1 JOIN)THE)COVERSATION rearrangement)(NCT03011372) Connect+with+us.

Myeloid/lymphoid neoplasms with a rearrangement of the FGFR1 gene located at 8p11.2 represent an exceedingly rare but aggressive malignancy with no standard treatment options and a dismal prognosis. Eosinophilia is usually present and should trigger testing for rearrangements involving FGFR1, and also PDGFRα and PDGFRβ. Verstovsek et al. (ASH 2018) reported a response rate of 85% in this ongoing pivotal trial (FIGHT203) of pemigatinib, an oral inhibitor of JOIN)OUR)MAILING)LIST FGFR1/2/3. If`you`would`like`to`receive` 2.)Avapritinib for)patients)with)advanced)systemic)mastocytosis an`electronic`issue`of`the` (NCT02561988) MD`Anderson`Leukemia`Insights` eYNewsletter`on`a`monthly` Virtually all cases of systemic mastocytosis (SM) are driven by basis,`please`complete`the` activating mutations at position D816 in the KIT gene. The median Subscription)Request)Form. survival of patients with AdvSM is reported to range from 2 months (for mast cell leukemia) to 3.5 years (for aggressive SM, ASM). The multiY It's`the`easiest`way`to`stay`current` kinase inhibitor midostaurin is approved for patients with AdvSM, but with`information`on`the`latest` leukemia`news,`research,`and` response rates by modern criteria are low, and the drug causes resources. myelosuppression and GI side effects. Avapritinib is a highly potent and selective inhibitor of mutant KIT. An overall response rate of 77% by modified IWGYMRTYECNM criteria was reported in the Phase 1 EXPLORER trial (Radia, EHA 2019). Avapritinib is now being studied CONTACT)OUR)STAFF in the Phase 2 PATHFINDER study in patients with AdvSM. Limited reimbursement to offset travel costs is available. Mary)Alma)Welch)Z Editor) Lisa Palacios)Z Publishing)Editor) [email protected] 3. KRT&232 for patients with previously treated, 7. Fedratinib for patients with MF who have failed high&risk PV (NCT03669965) ruxolitinib (NCT03755518)

MDM2 inhibition (by idasanutlin) has been shown to be The JAK2 inhibitor fedratinib was approved by the FDA effective in patients with high9risk PV who are resistant in August 2019 for the treatment of patients with MF. In to or intolerant of hydroxyurea (Mascarenhas, Blood a recent re9analysis of the JAKARTA92 trial employing 2019). KRT9232 is a highly potent, oral antagonist of stringent definitions of ruxolitinib refractoriness, the MDM29p53 interaction. The first part of this study resistance and intolerance, the rate of ≥35% spleen aims to select the best dose and schedule of KRT9232, volume reduction on fedratinib at 24 weeks was 30%, which is then taken into a randomized comparison and the rate of ≥50% reduction in total symptom score against ruxolitinib in the second part. To be eligible, was 27% (Harrison, ASCO 2019). FREEDOM is a patients must be resistant to or intolerant of Phase 3b, single9arm, open9label trial of fedratinib 400 hydroxyurea, or have previously received interferon. mg daily in patients who have “failed” ruxolitinib Prior ruxolitinib is not an exclusion. according to these new, stricter definitions.

4. PTG&300 for phlebotomy&requiring patients with 8. Pacritinib for patients with MF and platelets PV (NCT04057040) below 50 x 109/L (NCT03165734)

PTG9300 is a hepcidin mimetic that is administered by There is currently no approved therapy for patients with subcutaneous injection, initially weekly. This study MF and severe thrombocytopenia (platelets <50 x enrolls patients with PV who require phlebotomies 109/L), and these patients have a poor prognosis. (three or more, at least four weeks apart, within 24 Pacritinib is a relatively non9myelosuppressive JAK2 weeks prior to study entryP the most recent one should inhibitor that has been studied with mixed results in two be within eight weeks of study entry). For those on Phase 3 trials in patients with MF. A subsequent dose9 cytoreductive therapy (hydroxyurea, interferon, finding study in ruxolitinib9pretreated patients with MF ruxolitinib), the dose must be stable for ≥24 weeks with (PAC203) has completed accrual, and results are no planned change. expected later this year. PACIFICA, a pivotal trial of pacritinib versus physician’s choice (including low9dose 5. Sotatercept for patients with MF and anemia ruxolitinib) in patients with MF and platelets <50 x (NCT01712308) 109/L, will open soon.

Treatment options for anemia in patients with MF are 9. KRT&232 for patients with MF who have failed a limited, and the problem is often compounded by the JAK inhibitor (NCT03662126) use of JAK2 inhibitors, e.g., ruxolitinib or fedratinib. Sotatercept is a first9in9class activin receptor ligand trap Up9regulation of MDM2 by JAK2V617F supports MDM2 that improves anemia by sequestering ligands of the inhibition as a therapeutic strategy in JAK2V617F9driven TGFβ superfamily and preventing their interaction with neoplasms. Additionally, TGF9β is important in MF the activin receptor. In an investigator9initiated trial at pathophysiology and increases MDM2 expression. As MD Anderson, sotatercept produced a 35% response alluded to above, KRT9232 is a potent MDM2 inhibitor. rate (a mix of anemia response and transfusion Part 1 of this study aims to determine the optimal dose independence) in patients not on JAK inhibitor therapy and schedule of KRT9232 in patients with MF who have (Bose, EHA 2019). In patients on a stable dose of failed treatment with a JAK inhibitor. This dose will then ruxolitinib for ≥8 weeks, the response rate was 23%. be explored in a larger number of ruxolitinib9exposed Results are pending from a similar, industry9sponsored patients in the second part. trial of luspatercept, which is similar to sotatercept. 10. Tagraxofusp for patients with MF who have 6. Luspatercept for patients with MF and anemia failed a JAK inhibitor (NCT02268253) (NCT03194542) Tagraxofusp is a diphtheria toxin9containing, CD1239 A closely related congener of sotatercept, luspatercept targeting fusion protein recently approved for the demonstrated statistically significantly superior rates of treatment of blastic plasmacytoid dendritic cell transfusion independence in patients with MDS and neoplasm (BPDCN) that is also being studied in ringed sideroblasts in a pivotal trial (MEDALIST, patients with CMML and MF. CD1239expressing Fenaux, ASH 2018). As noted above, results from the plasmacytoid dendritic cells are present in the MF trial of luspatercept in patients with MF and anemia are microenvironment and may be tumor9promoting. The expected soon. One cohort from this trial (patients on a drug is administered IV on days 193 every 21 days in stable dose of ruxolitinib and red blood cell transfusion this Phase 1/2 study. Patients must be refractory to, dependent) is being expanded to gain more experience intolerant of or have relapsed on JAK inhibitor in this difficult group. therapy. Preliminary results (Pemmaraju, ASCO 2019) 13. PU&H71 added to ruxolitinib in patients with a demonstrate activity in terms of spleen size reduction sub&optimal response to ruxolitinib (NCT03935555) with a manageable safety profile. JAK2 is a “client” of the chaperone protein heat shock 11. CPI&0610 after, added to and with (in JAK protein 90 (HSP90)\ HSP90 inhibition, therefore, can inhibitor&naïve patients) ruxolitinib (NCT02158858) lead to degradation of JAK2, possibly affording a way to circumvent resistance to JAK2 inhibitors through the CPIF0610 is an orally administered inhibitor of “persistence” phenomenon (Bhagwat, Blood 2014). In bromodomain and extraFterminal (BET) proteins. BET the current trial, oral PHFH71 is being studied as an inhibitors synergize with ruxolitinib in preclinical models “add on” therapy in MF patients with a subFoptimal of MF by downFregulating numerous oncoproteins (NFF response to ruxolitinib. kappa B, cFMyc, BclF2 [Kleppe, Cancer Cell 2018]). The MANIFEST trial is studying CPIF0610 alone or added to 14. Ruxolitinib plus thalidomide in patients with MF ruxolitinib in patients who have had an insufficient (NCT03069326) response to the latter, and CPIF0610 in conjunction with ruxolitinib in patients not previously treated with a JAK Thrombocytopenia presents a particularly challenging inhibitor. Early results (Kremyanskaya, ASCO 2019, management problem in patients with MF and, like Hoffman, EHA 2019) are promising with activity anemia, is often worsened by ruxolitinib or fedratinib, observed in terms of spleen, symptom and anemia especially early on. Previous studies suggest efficacy responses, as well as some encouraging signals with of lowFdose thalidomide (50 mg daily) in ameliorating respect to bone marrow fibrosis improvement. thrombocytopenia. This twoFinstitution (MD Anderson/Memorial Sloan Kettering), investigatorF 12. Parsaclisib added to ruxolitinib in patients with initiated study enrolls patients with MF who are a sub&optimal response to ruxolitinib ruxolitinibFnaïve or have been on ruxolitinib for ≥3 (NCT02718300) months without having achieved a CR or PR per IWGF MRT criteria. Thalidomide is added after 12 weeks of Parsaclisib is an orally available, deltaFisoformFspecific ruxolitinib monotherapy in the former patients. Early inhibitor of PI3kinases. In this trial, parsaclisib is added results are promising, particularly platelet responses to ruxolitinib in patients with MF who have been on the (Rampal, ASH 2018, EHA 2019). latter drug for six months or more but who still have a spleen palpable ≥10 cm below the left costal margin or 5F10 cm with active symptoms of MF. Based on early data from this trial (Daver, ASH 2018), parsaclisib appears to have a good safety profile with fewer immuneFrelated toxicities than seen with other agents in this class.

FacultySContacts Completing+these+studies+in+a+timely+manner+will+allow+us+to+move+quickly+on+positive+leads.+We+appreciate+ referrals+and+will+make+every+effort,+once+a+patient+is+enrolled+on+a+study,+to+continue+as+much+of+the+care+as+ possible+through+the+referring+oncologist.+We+also+will+keep+you+apprised+of+the+patient's+progress. ClinicalSFaculty

Kantarjian,dHagop Department Chair (713)d792F7026

GarciaFManero,dGuillermo Deputy+Chair,+Chief,+Section+of+Translational+ (713)d745F3428 Research,+Chief,+Section+of+Myelodysplastic Syndromes+ (MDS),+and+Director,+Leukemia+Clinical+Fellowship+Program

Konopleva,dMarina Deputy+Chair,+and+Chief,+Section+of+Leukemia+ (713)d794F1628d Biology+Research

Wierda,dWilliam Deputy+Chair,+Chief,+Section+of+Chronic+Lymphocytic+ (713)d745F0428 Leukemia+(CLL),+and+Leukemia+Center+Medical+Director

Andreeff,dMichael Chief,+Section+of+Molecular+Hematology+and+Therapy, (713)d792F7261 CenterdMedicaldDirector,dBonedMarrowdAspirationdClinic Faculty(Contacts (Continued)

Borthakur,*Gautam Chief,'Section'of'Developmental'Therapeutics (713)*56341586

DiNardo,*Courtney*D. Co7Leader,'Section'of'Acute'Myeloid'Leukemia'(AML),' (734)*35841053 Co7Leader,'Section'of'Developmental'Therapeutics Leader,'Hereditary'Hematologic'Malignancy'Clinic'

Ferrajoli,*Alessandra Leukemia'Center'Associate'Medical'Director (713)*79242063*

Jabbour,*Elias Chief,'Section'of'Acute'Lymphoblastic'Leukemia'(ALL) (713)*79244764

Naqvi,*Kiran Co7Leader,'Section'of'Chronic'Myeloid'Leukemia'(CML)' (713)*74545073

Kadia,*Tapan Co7Leader,'Section'of'Acute'Myeloid'Leukemia'(AML),' (713)*56343534* Co7Leader,'Section'of'Developmental'Therapeutics,' Co7Leader,'Leukemia'Clinical'Fellowship'Program

Ravandi,*Farhad Chief,'Section'of'Acute'Myeloid'Leukemia'(AML) (281)*21647806

Sasaki,*Koji Co7Leader,'Section'of'Chronic'Myeloid'Leukemia'(CML) (713)*74542882

Verstovsek,*Srdan Chief,'Section'of'Myeloproliferative'Neoplasms'(MPNs),' 713)*74543429 Director,'Clinical'Research'Center'for'MPNs

Clinical(Faculty Research(Faculty Alvarado,*Yesid (713)*79444364 Battula,*Venkata (713)*56342227 Bose,*Prithviraj (713)*79247747 Bhalla,*Kapil*N. (713)*56348619 Burger,*Jan (713)*56341487 Burks,*Jared*K. (713)*79247640 Daver,*Naval (713)*79444392 Carter,*Bing*Z. (713)*79444014 Estrov,*Zeev (713)*79441675 Chang,*Kyung*Hee (713)*79244694 Issa,*Ghayas*"Gus” (713)*74548432 Colla,*Simona (713)*79445223 Jain,*Nitin (713)*74546080 Fiskus,*Warren (713)*56345901 Kornblau,*Steven (713)*79441568 Freireich,*Emil (713)*79242660 Masarova,*Lucia (832)*75044211 Gandhi,*Varsha*V. (713)*79242989 Montalban*Bravo,*Guillermo (713)*79443604 Han,*Lina (713)*79247640 Ohanian,*Maro (713)*79240091 Ishizawa,*Jo (713)*79247640 Pemmaraju,*Naveen (713)*79244956 Keating,*Michael (713)*74542376 Short,*Nicholas (713)*56344485 Piya,*Sujan (713)*79247305 Takahashi,*Koichi (713)*74544613 Plunkett,*William (713)*79243335 Thompson,*Philip (713)*79247430 Post,*Sean (713)*79441458 Yilmaz,*Musa (713)*74549945 Pourebrahimabadi,*Rasoul (713)*79247305 Rytting,*Michael*E. (713)*79244855 Ruvolo,*Peter (713)*74549211 Wei,*Yue (713)*79249854 Yang,*Hui (713)*79242558 Zhang,*Weiguo (713)*79444085

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