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11.12.2. reporting of serious adverse

Serious adverse events (SAE) including death (except deaths due to disease progression) during this study or within 30 days following the last dose of the study drug(s), whether or not related to the administration of study drugs, must be reported to the Yale Project Manager and Sponsor PI (Dr. Amer Zeidan) by telephone or email **within 24 hours of knowledge of the event**.  
The study site should send the SAE form to the Yale Project Manager and Sponsor PI as soon as possible so that the tracking procedure can begin immediately upon receipt of the information. Once the Yale Project Manager and Sponsor PI are informed of an SAE with preliminary information obtained, the study site will be instructed to update the SAE form with additional information, as per the following guidelines. If all information is not known at the time of the incident, an initial report should still be made. In the event there is a question as to whether the event is serious, the information should be forwarded to the Yale Project Manager and Sponsor PI for review. Each Site PI is responsible for following up on completion of the SAE
form. The Investigator will submit substantiating data in hard copy form, such as diagnostic test reports and progress notes, to the Yale Project Manager and Sponsor PI. In the case of fatality, autopsy reports will be furnished to the Yale Project Manager and Sponsor PI as soon as available. During the initial communication, the Yale Project Manager will require the following information about the patient and the reported SAE:  
- patient identification including patient number, initials, and date of birth;
- date of first dose of study drugs and details of administration, including study drug names
(including labeled strength and manufacturer), lot number, expiration date, and dose;
- date of last dose of study drugs (i.e., prior to onset of SAE) and details of administration, including study drug names (including labeled strength and manufacturer, lot number, expiration date, and dose);
- medical diagnosis of the event in standard medical terminology (if a medical diagnosis cannot be determined, a description of each sign or symptom characterizing the event);
- date of onset of the AE; - date of resolution of the AE (or confirmation ongoing); - severity of the AE;
- assessment of the attribution of the AE to the study drug;
- reason AE is considered serious
- whether the AE is expected
- action taken in treating the AE and/or change in study drug administration or dose (including concomitant medications or therapies administered, whether hospitalization or prolongation of hospitalization was required, diagnostic procedures performed, and whether the patient was
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page 60 of 79

discontinued from the study); all concomitant medications (including doses, routes, regimens, and indications);
- pertinent clinical laboratory testing data;
- medical history.  
The Yale Project Manager and Sponsor PI will review each SAE report and evaluate the relationship of the adverse reaction to the study drug and to the underlying disease. Based on the Investigator's and Sponsor PI assessment of the adverse experience, a decision will be made concerning further actions. The primary consideration governing further action is whether new findings affect the safety of patients participating in the clinical study. If the discovery of a new adverse experience related to the study drug raises concern over the safety of continued administration of study drug, the Sponsor PI will take immediate steps to notify the regulatory authorities.  
Further action that may be required includes the following:
- modification of the protocol and alteration of existing research plans;
- discontinuation or suspension of the study;
- alteration of the informed consent process by modification of the existing consent form and informing current study participants of new findings;
- modification of previously identified expected adverse experiences to include adverse experiences newly identified as study medication-related.
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11.12.3. reporting to the irb

Sites are responsible for reporting to their IRB per local policy.
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11.12.4. reporting to external regulatory

The Yale Project Manager shall report all SAEs to the drug manufacturer and the FDA, as required. SAE will be reported to Pfizer based on the following timeline, when required.  
- within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least one fatal or immediately life-threatening event;
- within ten (10) calendar days upon receipt of any other initial and follow-up SAEs
Pfizer Inc at 1-800-438-1985 SAEs will be reported to the FDA based on the following timeline, when required.  
There are two types of expedited safety reports to the FDA:
1. 7-Calendar-Day FDA Telephone or Fax Report: The sponsor-investigator will directly notify the FDA, within 7 calendar days after his initial receipt of the information, of any adverse event that is ALL of the following:  
  
Notification to the FDA will be made directly to the new drug review division in the Center for Drug Evaluation and Research or in the product review division for the Center for Biologics Evaluation and Research, whichever was responsible for the review of the IND. [21CFR312.32(c)] A written report of the event is to follow within 15 calendar days.  
2. 15-Calendar-Day FDA Written Report: The sponsor-investigator will directly notify the FDA
within 15 calendar days of any adverse event that is ALL of the following:  
| Serious(due to non-fatal and non-life threatening criteria Unexpected Associated with the use of study drug   |
|---------------------------------------------------------------------------------------------------------------|  
  
Note: Serious Adverse Events which do not meet the criteria for expedited reporting will be reported to the FDA in the IND Annual Report.
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12. data analysis/statistical methods 12.1.

Using a historical CR rate of 17% for decitabine 20 mg/m2 on the standard of care five-day schedule
(based on the largest randomized study of decitabine in older patients with AML [DACO-16]), a minimum acceptable CR rate of 25% (given the addition of glasdegib and potential additional toxicity) and ultimately a predicted minimum CR rate of 47% (the alternative hypothesis) for patients accrued to either arm of the proposed randomized phase 2 study, a minimum of 23 evaluable patients per arm will be accrued to test for a statistically-significant difference with an 80% power and a 90% confidence interval
(which is equivalent to a type 1 error rate, alpha one-sided of 0.05).
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12.2. futility analysis

The separate, Simon two-stage minimax decision rule is to stop enrollment in either arm if 2 or fewer patients in that arm achieve CR of the 10 patients required to be accrued during the stage 1 portion of the study. The same null hypothesis will be applied to both treatment arms, separately, without correction for multiplicity. The probability of early termination is 0.53 in each arm, under the null hypothesis. After the first 10 patients are enrolled and futility analysis of each arm allowed continued enrollment, the second stage of the study will be conducted. If 8 of fewer responses are observed in an arm by the end of the second stage of the study then no further investigation of the drug combination is warranted in that arm.  
Accrual will be increased by 10% (a minimum total of 51 patients) to account for those patients that are anticipated to be unevaluable and maintain the integrity of the statistical design.
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12.3. analysis populations 12.3.1. full

The FAS will include all enrolled patients who received at least one dose of any study treatment (glasdegib or decitabine). This will be the primary analysis population for evaluating efficacy endpoints and patient characteristics.
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12.3.2. safety analysis set

The safety analysis set will include all patients who receive at least one dose of any study treatment
(glasdegib). It will be the primary analysis population for evaluating treatment administration/compliance and safety endpoints.
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12.4. efficacy analysis

Efficacy analyses will use the FAS. All CI for binary endpoint will use the exact method, unless otherwise stated.
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12.4.1. complete response

The proportion of patients achieving CR/CRi is the primary endpoint. The final analyses will be performed after all patients have been followed for at least 24 weeks.  
The proportion and two-sided 95% CI of patients achieving CR/CRi will be provided.
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12.4.2. response rate

The proportion of patients achieving response (CR/CRi + PR) is a secondary endpoint. A confirmation of response (Peripheral Blood only) is required 4 weeks after the first assessment per ELN 2017. The final analyses will be conducted after all patients have been followed for 24 weeks (to allow for confirmation of response per ELN 2017). The proportion and two-sided 95% CI (using exact method) of patients achieving response (CR/CRi + PR) will be provided.
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12.4.3. overall survival

Overall survival (OS) is defined as the time from date of first study treatment to date of death due to any cause. Patients last known to be alive will be censored at the date of last contact.  
OS will be analyzed and displayed graphically for each arm separately using the Kaplan-Meier method.  
The median event time for each arm and corresponding two-sided 95% CI will be provided. The KaplanMeier estimate of survival probabilities at 12, 18, and 24 months and their two-sided 95% CI (using loglog transformation and back-transformation) will be provided for each arm separately.  
First, OS will be analyzed when the primary endpoint of CR is analyzed in each respective arm. A followup analysis of updated OS will be conducted when the study concludes. OS is defined as the date of the first dose of any of the study medications to the date of death from any cause.
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12.4.4. duration of response

Duration of Response (DoR) is only patients achieving a CR. DoR is defined as the duration from date of first achieving CR to the date of disease relapse after CR or death due to any cause. Patients last known to be alive who are free from disease progression or relapse after CR are censored at the date of the last assessment that verifies their disease status. DoR will be analyzed and displayed graphically for each arm separately using the Kaplan-Meier method. The median DoR and corresponding two-sided 95% CI will be provided.
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12.4.5. time to response

Time to response (TTR) is only defined for patients who have ever achieved response on study as the time from date of the first dose of study drug to date of the first documentation of response (CR+PR). TTR will be analyzed and displayed graphically for each arm separately using the Kaplan-Meier method. The median TTR and corresponding two-sided 95% CI will be provided.
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12.4.6. other efficacy measures

Additional efficacy measures of interest include CR with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh), morphologic leukemia-free state (MLFS), PR, SD,
Cytogenetic CR (CRc), and molecular CR (CRm) per **Appendix 1**. The proportion of patients ever achieving each of the endpoints for the respective arm will be estimated with two-sided 95% CI
respectively.
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12.4.7. analysis of exploratory endpoints

CRMRD CRMRD negativity is assessed in CR and CRi patients only by central multiparameter flow cytometry (MFC) (**Appendix 1**). The proportion of patients who achieved CRMRD negativity and its 95% CI will be provided.
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12.5. safety analysis

Safety will be assessed primarily based on AEs. AEs will be tabulated by system organ class and preferred term (per Medical Dictionary for Regulatory Activities [MedDRA]), and will be further categorized by decitabine treatment arm (DAC5 and DAC10) and severity. The incidence for each AE will be provided as the total number of subjects that experienced the AE, as well as the percentage of the population that this represents. Incidence tables will be generated to summarize incidence of patients reporting at least one episode of each specific adverse event, incidence of adverse events causing withdrawals and incidence of serious adverse events. Listing of adverse events by patients will include the time to onset, the duration of each event, the severity of each event, and the relationship of the event to study therapy, whether it was a serious event, and whether it caused withdrawal. The adverse events rate will be estimated accompanied by an exact 95% confidence interval.
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12.5.1. stopping rules for unacceptable

Each of the treatment arms will have a separate stopping rule. Either arm may be discontinued for safety while the other continues to accrue. Specifically, either treatment arm will be discontinued when there is at least a 70% probability that the rate of any of the below pre-defined safety events of interest in that arm is above 25%  
- Treatment-related deaths that occur during study treatment through 28 days following the last dose of any study treatment, or the beginning of another anti-cancer therapy, whichever occurs first.  
- Drug-induced liver injury (Hy's Law cases), confirmed as detailed in Section 8.6.2, that occurs during study treatment through 28 days following the last dose of any study treatment, or the beginning of another anti-cancer therapy, whichever occurs first.  
- Grade ≥3 non-hematologic treatment-related AEs except for;
The safety stopping criteria will be applied within each arm starting when at least 10 patients have completed one cycle or experienced an unacceptable toxicity, and continuously thereafter. Enrollment will continue unless the stopping boundary is crossed. Patients who have completed at least one cycle or have experienced a pre-defined unacceptable toxicity will be included in the safety decision making. The two arms will be analyzed independently.  
Page 64 of 79  
o Grade 3 electrolyte abnormalities or LFT abnormalities that resolve to baseline or ≤  
Grade 1 within 7 days  
o Grade 3 nausea or vomiting that does not require/prolong hospitalization or require NGT  
feeding/TPN  
- Grade 4 treatment-related neutropenia (ANC<500/mm3) lasting ≥42 days from the start of each  
cycle without evidence of active AML  
| Accrued Sample Size*                                                                                                                                    | Maximum number of  unacceptable toxicities to  continue treatment arm**   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|
| Up to -11                                                                                                                                               | 3                                                                         |
| 12-14                                                                                                                                                   | 4                                                                         |
| 15-18                                                                                                                                                   | 5                                                                         |
| 19-21                                                                                                                                                   | 6                                                                         |
| 22-25 (full enrollment)                                                                                                                                 | 7                                                                         |
| * Patients who have completed 24 weeks or who have  experienced an unacceptable toxicity ** A weak prior of Beta (0.5,0.5) was used in the calculation. |                                                                           |  
If the safety stopping rule is met, accrual to the affected arm will be temporarily suspended in order to conduct a review of safety data. If after review, a safety issue is identified and can be corrected, the protocol will be amended accordingly and enrollment will restart to that arm.
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12.6. monitoring

The Sponsor PI or an appointed designee must be allowed to visit all study site locations periodically to assess the data quality and study integrity. On-site they will review study records and directly compare them with source documents, discuss the conduct of the study with the investigator, review regulatory and essential documents, review the investigational product, and verify that the facilities remain compliant.  
In addition, remote monitoring of data may be performed periodically requiring the site to submit data for comparison to the OnCore database. The study will also be reviewed by the Yale University DSMC and may be reviewed by Yale's internal auditors. Yale University DSMC letters will be provided to external sites as evidence of continued oversight.
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13. data handling and record

As used in this protocol, the term CRF should be understood to refer to either a paper form or an electronic data record or both, depending on the data collection method used in this study. A CRF is required and should be completed for each included patient.  
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety and laboratory data entered on the CRFs and any other data collection forms (source documents) and ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, timely
(contemporaneous), enduring and available when required. Any corrections to entries made in the CRFs or source documents must be dated, initialed and explained (if necessary) and should not obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's patient chart. In these cases, data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.
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13.2. record retention

To enable evaluations and/or audits from regulatory authorities or Yale, the investigator agrees to keep records, including the identity of all participating patients (sufficient information to link records, e.g. CRFs and hospital records), all original signed informed consent/assent documents, copies of all CRFs, safety reporting forms, source documents, and detailed records of treatment disposition, and adequate documentation of relevant correspondence (e.g. letters, meeting minutes, and telephone call reports). The records should be retained by the investigator according to International Conference on Harmonization
(ICH), according to local regulations, or as specified in the clinical study agreement (CSA), whichever is longer. If the investigator becomes unable for any reason to continue to retain study records for the required period (e.g. retirement, relocation), Yale should be prospectively notified.
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14. ethics 14.1. ethical principles

This study will be conducted in accordance with the consensus ethical principles derived from international guidelines including the Declaration of Helsinki; applicable Good Clinical Practice (GCP) Guidelines published by the International Conference on Harmonisation; and applicable US laws and regulations including those found in 21 CFR Parts 50, 54, 56, and 312.
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14.2. institutional review board (irb)/ethics

It is the responsibility of the investigator to have prospective approval of the study protocol, protocol amendments, informed consent/assent documents, and other relevant documents, e.g. recruitment advertisements, if applicable, from the IRB/EC. All correspondence with the IRB/EC should be retained in the investigator file. Copies of IRB/EC approvals should be forwarded to the Project Manager. The only circumstance in which an amendment may be initiated prior to IRB/EC approval is where the change is necessary to eliminate apparent immediate hazards to the patients.
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14.3. financial disclosure

Investigators and sub-investigators will provide the Sponsor PI with sufficient, accurate financial information as requested to allow the sponsor to submit complete and accurate financial certification or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for providing information on financial interests during the course of the study and for 1 year after completion of the study
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15. references

1. O'Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:926-57.  
2. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and geneexpression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109:431-48. 3. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075-83.  
4. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98:131220. 5. Medeiros BC, Othus M, Fang M, Roulston D, Appelbaum FR. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience.  
Blood. 2010;116:2224-8. 6. Perrot A, Luquet I, Pigneux A, Mugneret F, Delaunay J, Harousseau JL, et al. Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood. 2011;118:679-85. 7. Kadia TM, Jain P, Ravandi F, Garcia-Manero G, Andreef M, Takahashi K, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.  
Cancer. 2016. 8. Middeke JM, Herold S, Rucker-Braun E, Berdel WE, Stelljes M, Kaufmann M, et al. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2016;172:914-22. 9. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell. 2008;15:801-12.  
10. Dominguez M, Brunner M, Hafen E, Basler K. Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitus interruptus. Science. 1996;272:1621-5. 11. Lim Y, Matsui W. Hedgehog signaling in hematopoiesis. Crit Rev Eukaryot Gene Expr. 2010;20:129-39.  
12. Trowbridge JJ, Scott MP, Bhatia M. Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci U S A. 2006;103:14134-9. 13. Kobune M, Takimoto R, Murase K, Iyama S, Sato T, Kikuchi S, et al. Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells. Cancer Sci. 2009;100:948-55.  
14. Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, et al. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci. 2016;107:1422-9. 15. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119:2196-204.  
16. Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, et al. Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017;108:1628-33.  
17. Wellbrock J, Latuske E, Kohler J, Wagner K, Stamm H, Vettorazzi E, et al. Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects. Clin Cancer Res. 2015;21:2388-98.  
18. Martinelli G, Oehler VG, Papayannidis C, Courtney R, Shaik MN, Zhang X, et al. Treatment with PF04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol. 2015;2:e339-46.  
19. Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556-61.  
20. Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010;107:7473-8.  
21. Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016;375:2023-36.  
22. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30:2670-7.  
23. Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, et al. Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or HighRisk MDS. Clin Cancer Res. 2018;24:2294-303.  
24. Boddu P, Kantarjian H, Ravandi F, Garcia-Manero G, Borthakur G, Andreeff M, et al. Outcomes with lower intensity therapy in TP53-mutated acute myeloid leukemia. Leuk Lymphoma. 2018:1-4.  
25. Short NJ, Kantarjian HM, Garcia-Manero G, Borthakur G, Kadia T, Huang X, et al. A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia. Blood. 2017;130:2577-.  
26. Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T, et al. A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome. Blood. 2016;128:99-.  
27. Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018;93:1301-10.  
28. Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635-40.  
29. Shaik MN, LaBadie RR, Rudin D, Levin WJ. Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers. Cancer Chemother Pharmacol. 2014;74:411-8. 30. Lam JL, Vaz A, Hee B, Liang Y, Yang X, Shaik MN. Metabolism, excretion and pharmacokinetics of
[(14)C]glasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica.  
2017;47:1064-76.
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appendices

Appendix 1. 2017 ELN Response Criteria for Acute Myeloid Leukemia  
| Category                                                          | Definition                                                       | Comment                                                   |
|-------------------------------------------------------------------|------------------------------------------------------------------|-----------------------------------------------------------|
| Response                                                          |                                                                  |                                                           |
| CR without minimal residual                                       | If studied pretreatment, CR with negativity for a genetic marker | Sensitivities vary by marker tested, and by method        |
| disease (CRMBD-)                                                  | by RT-qPCR, or CR with negativity by MFC                         | used; therefore, test used and sensitivity of the         |
| assay should be reported; analyses should be done                 |                                                                  |                                                           |
| in experienced laboratories (centralized diagnostics)             |                                                                  |                                                           |
| Complete remission (CR)                                           | Bone marrow blasts <5%; absence of circulating blasts and        | MRD thor unknown                                          |
| blasts with Auer rods; absence of extramedullary disease;         |                                                                  |                                                           |
| ANC ≥ 1.0 × 10 9 /L (1000/ µ L); platelet count ≥ 100 × 10 9 /L   |                                                                  |                                                           |
| (100 000/μ L)                                                     |                                                                  |                                                           |
| CR with incomplete                                                | All CR criteria except for residual neutropenia (< 1.0 × 10 9 /L |                                                           |
| hematologic recovery                                              | [1000/ L ]) or thrombocytopenia (<100 x 10 3 /L [10000/ L ])     |                                                           |
| (CR)                                                              |                                                                  |                                                           |
| Morphologic leukemia-free                                         | Bone marrow blasts <5%; absence of blasts with Auer rods;        | Marrow should not merely be "aplastic"; at least 200      |
| state (MLFS)                                                      | absence of extramedullary disease; no hematologic recovery       | cells should be enumerated or cellularity should be       |
| required                                                          | at least 10%                                                     |                                                           |
| Partial remission (PR)                                            | All hematologic criteria of CR; decrease of bone marrow blast    | Especially important in the context of phase 1-2 clinical |
| percentage to 5% to 25%; and decrease of pretreatment             | trials                                                           |                                                           |
| bone marrow blast percentage by at least 50%                      |                                                                  |                                                           |
| Treatment failure                                                 |                                                                  |                                                           |
| Primary refractory disease                                        | No CR or CR, after 2 courses of intensive induction treatment;   | Regimens containing higher doses of cytarabine (see       |
| excluding patients with death in aplasia or death due to          | Table 8) are generally considered as the best option             |                                                           |
| indeterminate cause                                               | for patients not responding to a first cycle of 7+3; the         |                                                           |
| likelihood of responding to such regimens is lower                |                                                                  |                                                           |
| after failure of a first                                          |                                                                  |                                                           |
| Death in aplasia                                                  | Deaths occurring ≥ 7 d following completion of initial treatment |                                                           |
| while cytopenic; with an aplastic or hypoplastic bone marrow      |                                                                  |                                                           |
| obtained within 7 d of death, without evidence of persistent      |                                                                  |                                                           |
| leukemia                                                          |                                                                  |                                                           |
| Death from indeterminate                                          | Deaths occurring before completion of therapy, or <7 d           |                                                           |
| cuse                                                              | following its completion; or deaths occurring ≥ 7 d following    |                                                           |
| completion of initial therapy with no blasts in the blood, but no |                                                                  |                                                           |
| bone marrow examination available                                 |                                                                  |                                                           |
| Page 69 of 79                                                     |                                                                  |                                                           |
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appendix 1. 2017 eln response

| Response criteria for clinical                                                                                               |                                                             |                                                           |
|------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|-----------------------------------------------------------|
| trials only                                                                                                                  |                                                             |                                                           |
| Stable disease                                                                                                               | Absence of CRMRD-, CR, CR, PR, MLFS; and criteria for PD    | Period of stable disease should last at least 3 mo        |
| not met                                                                                                                      |                                                             |                                                           |
| Progressive disease (PD)*.†                                                                                                  | Evidence for an increase in bone marrow blast percentage    | Category mainly applies for older patient given low¬      |
| and/or increase of absolute blast counts in the blood:                                                                       | intensity or single-agent "targeted therapies" in           |                                                           |
| clinical trials                                                                                                              |                                                             |                                                           |
| - >50% increase in marrow blasts over baseline (a minimum                                                                    | In general, at least 2 cycles of a novel agent should be    |                                                           |
| 15% point increase is required in cases with <30% blasts at                                                                  | aministered                                                 |                                                           |
| baseline; or persistent marrow blast percentage of > 70%                                                                     | Some protocols may require blast increase in 2              |                                                           |
| over at least 3 mo; without at least a 100% improvement in                                                                   | consecutive marrow assessments at least 4 wk                |                                                           |
| ANC to an absolute level (>0.5 × 10 9 /L [500/μL], and/or                                                                    | apart; the date of progression should then be defined       |                                                           |
| platelet count to >50 × 10 9 /L [50 000/μL] nontransfused); or                                                               | as of the first observation date                            |                                                           |
| - >50% increase in peripheral blasts (WBC × % blasts) to                                                                     | Some protocols may allow transient addition of              |                                                           |
| >25 × 10 9 /L (>25 000/ L ) (in the absence of differentiation                                                               | hydroxyurea to lower blast counts                           |                                                           |
| syndrome)†; or                                                                                                               | "Progressive disease" is usually accompanied by a           |                                                           |
| - New extramedullary disease                                                                                                 | decline in ANC and platelets and increased                  |                                                           |
| transfusion requirement and decline in performance                                                                           |                                                             |                                                           |
| status or increase in symptoms                                                                                               |                                                             |                                                           |
| Relapse                                                                                                                      |                                                             |                                                           |
| Hematologic relapse                                                                                                          | Bone marrow blasts ≥ 5%; or reappearance of blasts in the   |                                                           |
| (after CRMBD-, CR, CR,)                                                                                                      | blood; or development of extramedullary disease             |                                                           |
| Molecular relapse                                                                                                            | If studied pretreatment, reoccurrence of MRD as assessed by | Test applied, sensitivity of the assay, and cutoff values |
| (fter CRMBD-)                                                                                                                | RT-gPCR or by MFC                                           | used must be reported; analyses should be done in         |
| experienced laboratories (centralized diagnostics)                                                                           |                                                             |                                                           |
| ANC, absolute neutrophil count; IDH, isocitrate dehydrogenase; MLFS, morphologic leukemia-free state; WBC, white blood cell. |                                                             |                                                           |  
*The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at harmonizing the various definitions used in different clinical trials †Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, that is, a transient increase in the percentage of bone marrow blasts and an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD.  
Source: Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–447.  
| Strong CYP3A4/5 Inducers Inducer Therapeutic Class Rifampin Antibiotics Rifabutin Antibiotics Avasimibe Antilipedimics Phenytoin Anticonvulsants Carbamazepine Anticonvulsants Phenobarbital Anticonvulsants Enzalutamide Antiandrogens St. John's Wort Herbal Medications Mitotane Antineoplastics Moderate CYP3A4/5 Inducers Inducer Therapeutic Class Semagacestat Alzheimer's  Efavirenz Non-nucleoside  Reverse  Transcriptase  Inhibitors (NNRTI) Bosentan Endothelin Receptor  Antagonist Genistein Food Product Thioridazine Antipsychotics Naficillin Antibiotics Talviraline NNRTI Lopinavir Protease Inhibitor Modafinil Psychostimulant Etravirine NNRTI Lersivirine NNRTI   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Source: University of Washington Drug Interaction Database. "Copyright University of Washington 1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: November 2018".  
| Inhibitor              | Therapeutic Class       |
|------------------------|-------------------------|
| Ketoconazole           | Antifungal              |
| Itraconazole           | Antifungal              |
| Voriconazole           | Antifungal              |
| Posaconazole           | Antifungal              |
| Troleandomycin         | Antibiotics             |
| Clarithromycin         | Antibiotics             |
| Telithromycin          | Antibiotics             |
| Mibefradil             | Calcium Channel Blocker |
| Conivaptan             | Diuretics               |
| Nefazodone             | Antidepressants         |
| Cobicistat             | --                      |
| Indinavir/Ritonavir    | Protease Inhibitors     |
| Tipranavir/Ritonavir   | Protease Inhibitors     |
| Ritonavir              | Protease Inhibitors     |
| Indinavir              | Protease Inhibitors     |
| Nelfinavir             | Protease Inhibitors     |
| Saquinavir             | Protease Inhibitors     |
| Saquinavir/Ritonavir   | Protease Inhibitors     |
| Lopinavir/Ritonavir    | Protease Inhibitors     |
| Telaprevir             | Antivirals              |
| Boceprevir             | Antivirals              |
| Danoprevir/Ritonavir   | Antivirals              |
| Elvitegravir/Ritonavir | Antivirals              |
| Idelalisib             | Kinase Inhibitors       |
| Grapefruit Juice DS    | Food Products           |  
Source: University of Washington Drug Interaction Database. "Copyright University of Washington 1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: November 2018".  
| Inhibitor            | Therapeutic Class        |
|----------------------|--------------------------|
| Fluconazole          | Antifungals              |
| Erythromycin         | Antibiotics              |
| Ciprofloxacin        | Antibiotics              |
| Diltiazem            | Calcium Channel Blockers |
| Verapamil            | Calcium Channel Blockers |
| Dronedarone          | Antiarrhythmics          |
| Aprepitant           | Antiemetics              |
| Casopitant           | Antiemetics              |
| Netupitant           | Antiemetics              |
| Tofisopam            | Benzodiazepines          |
| Cyclosporine         | Immunosuppressant        |
| Faldaprevir          | Antivirals               |
| Crizotinib           | Kinase Inhibitor         |
| Nilotinib            | Kinase Inhibitor         |
| Atazanivir/Ritonavir | Protease Inhibitor       |
| Darunavir            | Protease Inhibitor       |
| Darunavir/Ritonavir  | Protease Inhibitor       |
| Atazanavir           | Protease Inhibitor       |
| Amprenavir           | Protease Inhibitor       |
| Imatinib             | Antineoplastic           |
| Grapefruit Juice     | Food Products            |  
Source: University of Washington Drug Interaction Database. "Copyright University of Washington 1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: November 2018".
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appendix 5. list of drugs

The following drugs are known to have the risk of Torsade de Pointes due to QTc prolongation and their current use in combination with glasdegib is not recommended. If any of these drugs are considered to be medically necessary, then they should be used with caution in combination with glasdegib.  
| Generic Name                                                                         | Drug Class           | Therapeutic Use                     | Route           |
|--------------------------------------------------------------------------------------|----------------------|-------------------------------------|-----------------|
| Amiodarone                                                                           | Anti-arrhythmic      | Abnormal heart rhythm               | Oral, injection |
| Anagrelide                                                                           | Phosphodiesterase    | Thrombocythemia                     | Oral            |
| 3 inhibitor                                                                          |                      |                                     |                 |
| Arsenic trioxide                                                                     | Anti-cancer          | Leukemia                            | Injection       |
| Astemizole (Off US mkt)                                                              | Antihistamine        | Allergic rhinitis                   | Oral            |
| Azithromycin                                                                         | Antibiotic           | Bacterial infection                 | Oral, injection |
| Bepridil (Off US mkt)                                                                | Anti-anginal         | Heart pain                          | Oral            |
| Chloroquine                                                                          | Anti-malarial        | Malarial infection                  | Oral            |
| Chlorpromazine                                                                       | Anti                      |                                     |                 |
| psychotic/antiemetic                                                                                      | Schizophrenia/nausea | Oral, injection,  suppository       |                 |
| Cilostazol                                                                           | Phosphodiesterase    | Intermittent claudication           | Oral            |
| 3 inhibitor                                                                          |                      |                                     |                 |
| Ciprofloxacin                                                                        | Antibiotic           | Bacterial Infection                 | Oral, injection |
| Cisapride (Off US mkt)                                                               | GI stimulant         | Heartburn                           | Oral            |
| Citalopram                                                                           | Anti-depressant,     | Depression                          |                 |
| SSRI                                                                                 |                      |                                     |                 |
| Clarithromycin                                                                       | Antibiotic           | Bacterial infection                 | Oral            |
| Disopyramide                                                                         | Anti-arrhythmic      | Abnormal heart rhythm               | Oral            |
| Dofetilide                                                                           | Anti-arrhythmic      | Abnormal heart rhythm               | Oral            |
| Domperidone (Not on US                                                               | Anti-nausea          | Nausea                              | Oral, injection |
| mkt)                                                                                 |                      |                                     |                 |
| Donepezil                                                                            |                      |                                     |                 |
| Erythromycin Antibiotic  Bacterial infection;  increase GI motility oral,  injection | Cholinesterase       | Dementia                            | Oral            |
| inhibitor                                                                            |                      |                                     |                 |
| Dronedarone                                                                          | Anti-arrhythmic      | Atrial Fibrillation                 | Oral            |
| Droperidol                                                                           | Anti-psychotic /     | Anesthesia adjunct, nausea          | Injection       |
| Anti-emetic                                                                          |                      |                                     |                 |
| Escitalopram                                                                         | Anti-depressant,     | Major depression/ Anxiety disorders | Oral            |
| SSRI                                                                                 |                      |                                     |                 |
| Flecainide                                                                           | Anti-arrhythmic      | Abnormal heart rhythm               | Oral            |
| Fluconazole                                                                          | Anti-fungal          | Fungal infection                    | Oral, injection |
| Gatifloxacin (Off US mkt)                                                            | Antibiotic           | Bacterial infection                 | Oral, injection |
| Grepafloxacin (Off market                                                            | Antibiotic           | Bacterial infection                 | Oral            |
| worldwide)  Halofantrine                                                             | Anti-malarial        | Malaria infection                   | Oral            |
| Haloperidol                                                                          | Anti-psychotic       | Schizophrenia, agitation            | Oral, injection |
| Ibutilide                                                                            | Anti-arrhythmic      | Abnormal heart rhythm               | Injection       |
| Levofloxacin                                                                         | Antibiotic           | Bacterial infection                 | oral, injection |
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page 74 of 79

| Levomethadyl (Off US           | Opiate          | Pain control, narcotic dependence   | Oral               |
|--------------------------------|-----------------|-------------------------------------|--------------------|
| mkt)                           |                 |                                     |                    |
| Mesoridazine (Off US mkt)      | Anti-psychotic  | Schizophrenia                       | Oral               |
| Methadone                      | Opiate          | Pain control, narcotic dependence   | oral, injection    |
| Moxifloxacin                   | Antibiotic      | Bacterial infection                 | oral, injection    |
| Ondansetron                    | Anti-emetic     | Nausea, vomiting                    | oral, injection    |
| Pentamidine                    | Antibiotic      | Pneumocystis pneumonia              | injection, inhaled |
| Pimozide                       | Anti-psychotic  | Tourette's tics                     | oral               |
| Probucol (Off US mkt)          | Antilipemic     | Hypercholesterolemia                | oral               |
| Procainamide (Oral off US      | Anti-arrhythmic | Abnormal heart rhythm               | injection          |
| mkt)                           |                 |                                     |                    |
| Propofol                       | Anesthetic      | Anesthesia                          | injection          |
| Quinidine                      | Anti-arrhythmic | Abnormal heart rhythm               | oral, injection    |
| Sevoflurane                    | Anesthetic,     | Anesthesia                          | inhaled            |
| general                        |                 |                                     |                    |
| Sotalol                        | Anti-arrhythmic | Abnormal heart rhythm               | oral               |
| Sparfloxacin (Off US mkt)      | Antibiotic      | Bacterial infection                 | oral               |
| Sulpiride (Not on US mkt.)     | Anti-psychotic, | Schizophrenia                       | oral               |
| atypical                       |                 |                                     |                    |
| Terfenadine (Off US mkt)       | Antihistamine   | Allergic rhinitis                   | oral               |
| Thioridazine                   | Anti-psychotic  | Schizophrenia                       | oral               |
| Vandetanib                     | Anti-cancer     | Thyroid cancer                      | oral               |
| US mkt = United States Market. |                 |                                     |                    |  
Source: Credible Meds.org (http://crediblemeds.org/healthcare-providers/drug-list/?rf=All). TdP risk category filtered on Drugs with known TdP risk. Assessed 12 November 2018.  
| Hematology                                                                                                                  | Blood Chemistry   | Urinalysis (microscopic                                                                                                                                                  | Coagulation   |
|-----------------------------------------------------------------------------------------------------------------------------|-------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| analysis)                                                                                                                   | Tests             |                                                                                                                                                                          |               |
| Hemoglobin                                                                                                                  | ALT               | If urine dipstick is positive  for protein, perform  urinalysis (U/A) with microscopic. If U/A with  microscopic shows >2+  protein, collect 24-hour  urine for protein. | aPTT          |
| Platelets                                                                                                                   | AST               | Urine dipstick for urine                                                                                                                                                 |               |
| blood: If positive, collect a  U/A with microscopic (unless hematuria can be  explained by local bleeding  such as menses). | INR               |                                                                                                                                                                          |               |
| WBC                                                                                                                         | Alk Phos          | Specific Gravity                                                                                                                                                         |               |
| Neutrophils                                                                                                                 | Sodium            | PH                                                                                                                                                                       |               |
| Lymphocytes                                                                                                                 | Potassium         | Protein                                                                                                                                                                  |               |
| Monocytes                                                                                                                   | Magnesium         | Glucose                                                                                                                                                                  |               |
| Eosinophils                                                                                                                 | Chloride          | RBC                                                                                                                                                                      |               |
| Basophils                                                                                                                   | Calcium           | WBC                                                                                                                                                                      |               |
| Bands                                                                                                                       | Bicarbonate       | Ketones                                                                                                                                                                  |               |
| Blast Count                                                                                                                 | Total Bilirubin   | Leukocyte Esterase                                                                                                                                                       |               |
| Direct Bilirubin                                                                                                            | Casts             |                                                                                                                                                                          |               |
| BUN or Urea                                                                                                                 | Crystals          |                                                                                                                                                                          |               |
| Creatinine                                                                                                                  | Nitrate           |                                                                                                                                                                          |               |
| Uric Acid                                                                                                                   |                   |                                                                                                                                                                          |               |
| Glucose (non-fasting) Albumin Total Protein Phosphorus LDH CPK                                                              |                   |                                                                                                                                                                          |               |  
Appendix 6. Laboratory Assessments Appendix 7. Eastern Cooperative Oncology Group Performance Status
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ecog performance status

| Grade   | ECOG                                                                                                                                                      |
|---------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Fully active, able to carry on all pre-disease performance without restriction                                                                            |
| 1       | Restricted in physically strenuous activity but ambulatory and able to carry out work of a  light or sedentary nature, e.g. light house work, office work |
| 2       | Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and  about more than 50% of waking hours                           |
| 3       | Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours                                                                  |
| 4       | Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair                                                                       |
| 5       | Dead                                                                                                                                                      |  
Source: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.:
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649655, 1982.  
By the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.  
|  Risk Category ®                                                             | Genetic Abnormality               |
|------------------------------------------------------------------------------|-----------------------------------|
| Favorable                                                                    | t(8,21)(q22,q22.1); RUNX1-RUNX1T1 |
| inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11                         |                                   |
| Mutated NPM1 without FLT3-ITD or with FLT3-ITD ow(o)                         |                                   |
| Biallelic mutated CEBPA                                                      |                                   |
| Intermediate                                                                 | Mutated NPM1 and FLT3-ITD serv    |
| Wild type NPM1 without FLT3-ITD or with FLT3-ITD 6 m ( 6 ) (w/o adverse-     |                                   |
| risk genetic lesions)                                                        |                                   |
| t(9;11)(p21.3;q23.3); MLLT3-KMT2A°                                           |                                   |
| Cytogenetic abnormalities not classified as favorable or adverse             |                                   |
| Adverse                                                                      | t(6;9)(p23;q34.1); DEK-NUP214.    |
| t(v;11q23.3); KMT2A rearranged                                               |                                   |
| t(9;22)(q34.1;q11.2); BCR-ABL1                                               |                                   |
| inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EV11)                 |                                   |
| -5 or del(5q); -7; -17/abn(17p)                                              |                                   |
| Complex karyotype,® monosomal karyotype'                                     |                                   |
| Wild type NPM1 and FLT3-ITDhishin                                            |                                   |
| Mutated RUNX1°                                                               |                                   |
| Mutated ASXL 19                                                              |                                   |
| Mutated TP53                                                                 |                                   |
| Frequencies, response rates, and outcome measures should be reported by risk |                                   |  
category, and, if sufficient numbers are available, by specific genetic lesions indicated.  
*Prognostic impact of a marker is treatment-dependent and may change with new therapies.  
†Low, low allelic ratio (<0.5); high, high allelic ratio ( ≥ 0.5); semiquantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve "FLT3-ITD" divided by area under the curve."FLT3wild type"; recent studies indicate that AML with NPM1 mutation and FLT3-ITD low allelic ratio may also have a more favorable prognosis and patients should not routinely be assigned to allogeneic HCT. 57-59,77
‡The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent averse-risk gene mutations.  
§Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1.  
IDefined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). 116
¶These markers should not be used as an adverse prognostic marker if they cooccur with favorable-risk AML subtypes.  
\#TP53 mutations are significantly associated with AML with complex and monosomal karyotype. 37, 66-69 Source: Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424-447.
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appendix 9. 2016 world health

| AL and related neoplasms                                              | AML and related neoplasms (cont'd)              |
|-----------------------------------------------------------------------|-------------------------------------------------|
| AML with recurrent genetic abnormalities                              | Acute myelomonocytic leukemia                   |
| AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1                            | Acute monoblastic/monocytic leukemia            |
| AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11         | Pure erythroid leukemia#                        |
| Acute promyelocytic leukemia with PML-RARA*                           | Acute megakaryoblastic leukemia                 |
| AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2At                           | Acute basophilic leukemia                       |
| AML with t(6;9)(p23;q34.1); DEK-NUP214                                | Acute panmyelosis with myelofibrosis            |
| AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EV11) | Myeloid sarcoma                                 |
| AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1‡         | Myeloid proliferations related to Down syndrome |
| Provisional entity: AML with BCR-ABL1                                 | Transient abnormal myelopoiesis                 |
| AL with mutated NPM1§                                                 | Myeloid leukemia associated with Down           |
| syndrome                                                              |                                                 |
| AML with biallelic mutations of CEBPA§                                | Blastic plasmacytoid dendritic cell neoplasm    |
| Provisional entity: AML with mutated RUNX1                            | Acute leukemias of ambiguous lineage            |
| AML with myelodysplasia-related changesII                             | Acute undifferentiated leukemia                 |
| Therapy-related myeloid neoplasms                                     | MPAL with t(9;22)(q34.1;q11.2); BCR-ABL1**      |
| AL, NOS                                                               | MPAL with t(v;11q23.3); KMT2A rearranged        |
| AL with minimal differentiation                                       | MPAL, B/myeloid, NOS                            |
| MPAL, T/myeloid, NOS                                                  |                                                 |
| AML without maturation                                                |                                                 |
| AML with maturation                                                   |                                                 |  
Sources:
1. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN
recommendations from an international expert panel. Blood. 2017;129:424-447.  
2. Arber DA, Orazi A, Robert, H, et.al. The 2016revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood.  2016; 127(20): 2391-2405.