International herald tribune The son of the Polish Holocaust survivor who was the subject of Roman Polanski 's Oscar-winning film 'The Pianist' hailed the awards as a tribute to the victims of World War II. The academy 'appreciated the fate that befell my father, the total degradation of a well-known artist under war conditions,' said Andrzej Szpilman, a doctor who lives in Europe and who attended the Academy Award ceremony in Los Angeles. The film tells the story of Wladyslaw Szpilman, a Jewish pianist in Warsaw. It won three Oscars: best director; best actor, and best adapted screenplay. (Wednesday, March 26, 2003) Army Archered - senior columnist, Just for Variety Meanwhile, Roman Polanski's 'The Pianist' received a huge rave in the Jerusalem Post, with William E. Grim calling the film, 'undoubtedly the greatest Holocaust film of all time,' adding 'The Pianist' is a testament to the indefatigable spirit of life that refuses to go gentle into the night.'

He also notes Adrien Brody's performance as 'stunning.' How war transforms 'Pianist' For all of its devastating power, Roman Polanski's film The Pianist reaches a point where it doesn't entirely ring true. How could anybody emerge from five horrific years of hard labor and starvation in World War II Warsaw with such clean, crisp, emotionally unclouded renditions of Chopin?

The real-life Wladyslaw Szpilman, whose memoir was the basis of the film, didn't play that way. Even before hearing the two Szpilman discs that have hit the market amid the two-Oscar success of The Pianist, seasoned music lovers could have predicted that. Polish pianism of that period is more about shade than light. But anyone can understand that artistic expression, even the supposedly stationary world of classical music, cannot exist in a demilitarized zone, standing apart from world events.

Performances conceived, delivered and heard during a state of crisis, or in its aftermath, can be hugely different from those that are not. Szpilman's fellow musicians - whatever side they were on during the war - changed so much over the 1940s and after that the great masterpieces they performed seemed to rewrite themselves. You can hear it in before-and-after recordings, in which one conductor beefed up the militaristic brass, and another found a conduit for psychic pain in the music's dissonances. Similarly, the world changed after Sept. 11 - and for a while, so did the music-making.

How the current war will change what we hear remains to be, well, heard. You could argue that such changes have most to do with how we hear. But this is only partially true.

I made a point of listening to the Szpilman discs (one from the independent label BCI Eclipse and the other from the German branch of Sony Classical) before and after seeing the film. What I heard didn't change, but the film explained a few things. Szpilman, who died three years ago, was an artist of sterling pedigree, which all but guarantees his recordings won't be a redux of the David Helfgott-style compromised pianism heard in the wake of the 1996 film Shine. No, from the first notes of both Szpilman discs, you hear poetic, Old-World rubato and that warm blanket of piano tone that's missing from the film's soundtrack performances by Janusz Olejniczak.

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Most arresting is a 1960 reading of Schumann's Fantasy in C major, the middle movement, which reaches an utterly singular, harrowingly intense climax. Nobody can really say this reflects Szpilman's wartime hardships, but my intuition tells me, unmistakably, that only someone who has paid rent in the abyss could conceive such phrase readings. Nearly identical in their selection of works, the two discs differ mainly in Sony's inclusion of a CD-ROM video feature of the aging Szpilman playing Chopin's Nocturne in C sharp minor in 1980. That's where the film offers needed context. The dignity of the pianist's manner has infinitely more impact if you know that this is the piece he was playing when Polish Radio was destroyed by the Nazis and that he returned to five years later, after the Nazis had been destroyed. Without asking for the slightest bit of sympathy, he was recreating a moment that was emblematic for his country and all Jewish survivors of World War II.

David Patrick Stearns Philadelphia Courier Sun, Mar. LIBRARY JOURNAL - Best Books of 1999 WLADYSLAW SZPILMAN WINS ANNUAL JEWISH QUARTERLY-WINGATE NON FICTION PRIZE 2000 London - 3rd May 2000 - The judges of the annual Jewish Quarterly-Wingate Literary Prizes tonight awarded this year's Non Fiction Prize to Wladyslaw Szpilman for The Pianist (Phoenix / Golancz). The decision was announced by author and broadcaster Frank Delaney, chairman of the judges, who had selected it earlier this evening from a shortlists of four titles: 'When you read this book - and you must read it - you will never forget it. The subtext asks whether good people were on the side of the evil people and shows how the human spirit is enlarged by the knowledge of such people.' T he 'Palme d’Or', three 'Oscars' and various European film prizes were among the awards collected by 'The Pianist', Roman Polanski’s film based upon Wladyslaw Szpilman’s bestseller book 'The Pianist', dealing with his 'miraculous survival' (as he called it) in Warsaw during the German occupation and final destruction between 1939 and 1945. But there is more to Szpilman than being 'The Pianist'. He is increasingly being noticed as a composer, both of concert works and of music in a lighter vein.

To say that the music was Wladyslaw Szpilman's life-blood is more than just a poetic metaphor. The Polish composer and pianist literally owes his miraculous survival of the Holocaust to music. Born in the Polish town of Sosnowiec on 5 December 1911, after first piano lessons Wladyslaw Szpilman continued his piano studies at the Warsaw Conservatory under A. Michalowski and subsequently at the Academy of Arts (Akademie der Kuenste) in Berlin under Arthur Schnabel and Leonid Kreutzer. He also studied composition under Franz Schreker. In 1933, he returned to Warsaw where he quickly became a celebrated pianist and a composer of both classical and popular music.

On 1 April 1935 he entered Polish Radio, where he was working as a pianist performing both, classical and jazz music. The German invasion of Warsaw on 23 September 1939 put an untimely but temporary end to Szpilman's musical career when a bomb, dropped on the studios of Polish Radio, interrupted his performance of Chopin's Nocturne in C Sharp minor.

Yet despite the inevitable changes to his life, brought about by the onset of war, Szpilman refused to give up his music. His Concertino for piano and orchestra was composed while he was experiencing the hardships and deprivation of the Warsaw Getto in 1940. Time after time, Szpilman managed to escape the deportations. Even when he and his entire family were packed into cattle trucks to be sent off to Treblinka, the famous pianist was miraculously picked out and spared from the death camp. Parallel To Serial Conversion Simulink Scope. He fled to the Aryan part of the city and spent two long and agonising years in hiding, always assisted by loyal Polish friends. After the Warsaw Uprising he continued to lead the life of a recluse in the deserted ghost town.

Towards the end of the war, he was discovered by a German officer of the Wehrmacht, Wilm Hosenfeld, who saved his life after listening to the starved pianist play Chopin's C Sharp minor Nocturne on the out-of tune piano of his hiding-place. When Szpilman resumed his activities as the at Polish Radio in 1945, he did so by carrying on where he left off six years before: poignantly, he opened the first transmission of the station by playing, once again, Chopin's C Sharp minor Nocturne. From 1945 to 1963 he held the position of Director of Music at Polish Radio. During these years he composed several symphonic works and about 500 songs, many of which still are popular in Poland today, including some children's songs, as well as music for radio plays and film.

He also performed as a soloist and with the violinists Bronislaw Gimpel, Roman Totenberg, Ida Haendel and Henryk Szeryng. In 1963, he and Gimpel founded the Warsaw Piano Quintet with which Szpilman performed world-wide until 1986. Wladyslaw Szpilman died on 6 July 2000 in Warsaw.

Adrien Brody accepting the Oscar Award.' This film would not be possible without the blueprint provided by Wladyslaw Szpilman. This is a tribute to his survival'. The Pianist Directed by Roman Polanski Starring: Adrien Brody and an ensemble cast Director Roman Polanski is back with his best film since Chinatown.

In fact, The Pianist just might be Polanski's best film ever. It's that powerful.

Based on the autobiographical book by Wladyslaw Szpilman, The Pianist tells the story of Szpilman's struggle to survive the Nazi occupation of Poland during World War II. Szpilman, a talented Jewish pianist and composer, witnessed first-hand the horrors of the Warsaw ghetto. The Nazis used this notorious, walled slum to imprison Polish Jews until their 'resettlement' to concentration camps. While most of his Jewish relatives and friends perished in the Holocaust, Szpilman managed to survive through sheer force of will and a number of strokes of luck.

The film tells his heartbreaking survival story with unflinching honesty. There are many fine performances in The Pianist, but it is Adrien Brody's portrayal of Szpilman that carries the film. Brody (The Thin Red Line, Summer of Sam, etc.) gives a masterful performance in this film. At times, he says more with his sad eyes than any dialogue could ever provide. He fully deserves the Oscar nomination he recently received for this multi-layered performance.

It's hard to imagine a filmmaker better suited to direct The Pianist than Polanski. His grim, existential sense of irony works perfectly with Szpilman's story. Polanski's effective direction never falls out of step with the story. Steven Spielberg's film, Schindler's List, brilliantly captured the raw horror of the Holocaust, but The Pianist does even more than this. As well as the horror, Polanski's film also captures the tragic absurdity of the situation. In the most powerful example of this absurdity, Szpilman and his family watch from their window as Nazi thugs enter an apartment across the street and command a Jewish family to stand up from their dinner table. When an elderly and disabled family member fails to rise from his wheel chair, the Nazis calmly throw him off the apartment's balcony to his death below.

The horrific absurdity of this scene is mind-boggling. But it's also a typical Polanskian moment: In a Polanski film, the world can be a maliciously absurd place. The film's greatest achievement is that it portrays all of the horror and insanity of the Holocaust without ever losing a sense of hope. Despite facing unimaginable cruelty and hardship, most of the Jewish characters in the film never lose their humanity.

And that's the triumph of Wladyslaw Szpilman's story. - Kenneth Hann ( www.sceneanhheard.ca Vol. 02 - Issue 08 ). In tune with history The Pianist book is a vivid look at occupied Poland Author's son worked years to get it published F ilms, if they are resonant enough, have a way of sending people back to their source materials, a phenomenon for which the publishing industry is duly grateful.

Who was that character we see for a few seconds? What really happened after the events portrayed in the movie?

The truth is, we will never trust movies the way we tend to trust books to deliver the real story. A glance at the New York Times best seller list shows that Virginia Woolf's 1925 novel Mrs. Dalloway, the inspiration forThe Hours, is No.

11 on the fiction list and climbing. Catch Me If You Can, the memoirs of conman Frank Abagnale, The Gangs Of New York by Herbert Asbury (first published in 1928), and The Pianist by Wladyslaw Szpilman are non-fiction best sellers. The last of these is worth a closer look.

Before Roman Polanski's The Pianist became possibly the best film ever made about the Holocaust, before it won the Palme d'Or at Cannes and garnered seven Oscar nominations, this story of the against-all-odds survival of the Jewish musician in German-occupied Poland was a book with an unusual publishing history. Szpilman witnessed the full horror of the Warsaw Getto then saw his parents, sisters and brother forced by the SS into cattle cars bound for certain death in Treblinka. Miraculously pulled out of the lineup for the train and urged to flee by a Jewish collaborationist policeman, he was assigned to work on a building crew in the ghetto, then escaped and hid for more than two years in the progressively more starved and ruined city with the help of members of the Polish resistance. Near the end of the war, he was discovered in an attic and protected by a nameless Wehrmacht officer, who brought him bread and jam and an eiderdown for warmth. Szpilman, who died in 2000 at the age of 88, wrote down this amazing story immediately after the liberation of Poland, which gives it unparalleled authenticity. More remarkable is his complete lack of indignation, anger or self-pity in the telling. 'My father was told by a doctor that he should see a psychiatrist because of the trauma he went through.

Or he could do auto-therapy — writing it down,' Szpilman's son Andrzej explains over the phone from Hamburg, Germany. 'He was working as music director for Polish radio and he had a secretary. He dictated the book to her. It took him 3 1/2 months.' The memoir was published in Polish in 1946 as Smierc Miasta meaning Death Of A City, then went out of print. 'In the 1960s the director of a publishing house approached my father and said he would like to print the book again but he had to ask permission of the Communist Party central committee.

Download Rock File Manager For Blackberry 8520. Two weeks later, he came back and said the committee said `No.' They gave no reason, but I think they did not want to touch the question of minorities and also, the Soviets were supposed to be our friends.' The book, which ends with the kindly German army officer getting captured by Soviets, presents too complex a view of human nature for any dictatorship to stomach. Poles, Jews, Germans as well as the Russian liberators are all shown to be capable of evil as well as decency. In 1950, Wladyslaw Szpilman married a doctor, Halina Grzecznarowski, and had two sons.

Andrzej, 46, who plays the violin but is a dental surgeon by profession, is the more musical son, devoted to the memory of his father. (An elder, Christopher, is a history professor living in Japan.) That the book got a new lease on life after 50 years and found its way to Roman Polanski was due largely to Andrzej's persistence. Andrzej was living in Germany after the fall of communism in Poland, teaching dentistry at the university in Hamburg and producing records on the side. He recorded the poet Wolf Biermann, whom he describes as 'the German Bob Dylan,' and told him about his father. Biermann asked around and discovered that a Polish-German translator had, in fact, translated and published a couple of chapters from Szpilman's out-of-print book. 'I paid her to finish the whole book so that my friend Wolf could read it,' recalls Andrzej. 'I met a publisher in Hamburg at a party and told her I had a translation of the book, and it was available.

She said right away, `I'll take it,' he says. It came out in Germany in `98 with Biermann's epilogue.

Andrzej ran into a friend in Monte Carlo who told him of an English literary agent, Christopher Little, who might be able to arrange for British publication. Andrzej sent him the book, not realizing he had lucked out: Christopher Little, who represents J.K. Rowling, of Harry Potter fame, is the hottest British literary agent. The Pianist was translated by Anthea Bell and published by Victor Gollancz in 1999, with Wladyslaw and Andrzej coming to England for the book's launch. Picked as one of the year's best books by The Sunday Times, The Guardian and The Economist, The Pianist was sold by Christopher Little to 21 other countries including, at last, Poland. The book sold 320,000 copies in France and 200,000 in Poland, where Szpilman was best known as a composer of popular songs.

'If you ask me why I did it (republish his father's book) I felt we had to bring this message to the people,' says Andrzej. 'There is a strong ethnic nationalism coming back in Europe — this book is warning.' The current paperback version of the book (distributed in Canada by McArthur & Co.) includes extracts from the diary of Capt. Wilm Hosenfeld, a devout Catholic who, it turns out, saved several Jews besides Szpilman. It was from one of these other Jews that Szpilman learned his name in 1950 and tried to get him out of the prisoner-of-war camp in Russia, where he was tortured and died.

According to Andrzej Szpilman, Polanski's lawyer bought the book and sent it to Polanski with a note: 'Here is your next movie.' Little sold film rights to Polanski in Jan. 'We saw the movie for the first time in Cannes, with my mother and brother. My son, who is 10, had a very small part in it,' says Andrzej. 'It was very moving, a shock. Adrien Brody is very like my father. Since then I have seen it 15 times.

In Poland 3,500 people saw the premier and applauded for 20 minutes. The Polish president and prime minister were there.' Hosenfeld's children were also there. These days, Andrzej Szpilman has taken leave of his dental surgery practice to devote himself entirely to making sure his father's music legacy — three musicals, around 50 children's songs and 600 pop tunes — is not lost. He recently produced a CD with 12 of his father's songs sung in English by Montrealer Wendy Lands (Wendy Lands Sings The Music Of The Pianist, on the Hip-O label).

When the Germans bombed the radio building in Warsaw in 1939, Szpilman was in the middle of Chopin's Nocturne in C-sharp minor. He resumed playing it six years later when the war ended.

Sony has issued five CD's and CD sets of Szpilman playing Bach, Brahms, Schumann, Rachmaninoff and his beloved Chopin. In the post-war years, Wladyslaw Szpilman continued to perform classical music as part of a duo with the violinist Bronislaw Gimpel, and later with the Warsaw Piano Quintet until 1986. His belated fame as a memoirist will, ironically, assure his fame as a musician.

By JUDY STOFFMAN Toronto Star Mar. 1, 2003 Photo Jewish Journal Los Angeles 2003-01-17 Memory Through Music Wladyslaw Szpilman’s jazzier tunes have made their way onto a new CD, thanks to his son, Andrzej. By Naomi Pfefferman, Arts & Entertainment Editor When Andrzej Szpilman was 12, he furtively rummaged through a chest high on a shelf of a closed wardrobe in his Warsaw home. Inside the closet, he found 10 copies of a book and, recognizing his father as the author, hid one in his third-story bedroom. “I read it and received a shock,” said Andrzej Szpilman, 46, a dentist and record producer who immigrated to Germany in 1983. The book was “Death of a City,” his father, Wladyslaw’s, grittily brutal, dispassionate 1946 memoir of hiding in and around the Warsaw Ghetto. Since Roman Polanski turned the book into a searing film, “The Pianist” — which won four National Society of Film Critics Awards and is up for two Golden Globes on Sunday — Szpilman has become one of the best-known Holocaust survivors in history.

But on that fateful 1968 day, his dramatic story was news to his son. “He had never once spoken of his experience,” Andrzej Szpilman said.

“He never even told me he was Jewish. I think it hurt him to talk about it, because he survived and all his family perished.” More than three decades after he discovered “The Pianist” hidden in a wardrobe, Andrzej Szpilman has made it his mission to bring his father’s life story out of the closet, literally. In 1999, he spearheaded the reissue of the memoir, which had been banned by the communist regime and ultimately captivated Polanski. When Polanski’s screenplay depicted his father only as a virtuoso pianist, he produced CDs highlighting his father’s work as a classical composer and the author of more than 500 pop songs. The latest, “Wendy Lands Sings the Music of The Pianist Wladyslaw Szpilman,” recently released by Universal’s Hip-O Records, is a well-received collection of jazzy ditties Szpilman (1911-2000) wrote from the 1930s to the 1960s. “In the film, we see [Poles] helping my father because they knew his Chopin performances, but the real reason most people knew him and hid him was from his hit songs,” his son said.

“He owes his survival to this kind of music.” In April, with his friend, Sherman Heinig, a German music industry veteran based in Los Angeles, Andrzej Szpilman brought in producer/arranger John Leftwich, who had worked with Rickie Lee Jones. Together, they hired writers to create new, English-language lyrics and auditioned about 30 singers before selecting Canadian-born chanteuse Wendy Lands. The venture is unusual because few scripted films have been able to generate nonsoundtrack albums, according to Variety. Andrzej Szpilman said he initially invested his own money in the project because his father, while famous in Poland, never had the chance to promote his work in the West. “His career was essentially [stunted] by the Nazis and then the communists,” he said. “But it was painful for me that people thought of his music as only good enough for the Polish market.

It’s my ambition to make it popular to a worldwide audience. That’s one way I can honor his memory.” When Andrzej Szpilman began working on reissuing “The Pianist,” he said his father, then in his late 80s, wasn’t interested in the slightest. “He said, ‘Do whatever you want, but no one will read it,’” his son recalled. Instead, the book became a critically acclaimed bestseller published in 20 languages. Wladyslaw Szpilman did agree to help publicize the memoir by appearing at book signings and speaking to readers, the first time his son ever heard him talk about the war. “But it was strange,” he said. “He hadn’t read the book in 50 years — in fact he never re-read it — but when he spoke he used the exact same sentences he’d written in ‘46.

Like the book, his tone was detached. He sounded like a computer.” Nevertheless, the elder Szpilman was pleased when the book drew Polanski’s attention and that of Dr. Noreen Green, artistic director of the Los Angeles Jewish Symphony, who conducted the 2001 world premiere of a piece mentioned in the memoir. In the book, Szpilman describes a Gershwinesque “Concertino for Piano and Orchestra” he wrote while languishing in the Warsaw Ghetto. “What struck me was the discrepancy between the wonderful, optimistic music and the terrible conditions under which it was written,” Green said. Andrzej Szpilman — who included the piece on a CD, “Music Inspired by the Motion Picture ‘The Pianist’” — believes the breezy “Concertino” provides clues to his late father’s psychology.

So do the upbeat songs, featured on the Lands disc, Szpilman wrote during the Holocaust and the communist regime’s anti-Semitic purge of 1968. “My father didn’t like to talk about these things, but writing music was his way of coping,” his son said. “The Pianist’s Story” – An Evening With Andrzej Szpilman On May 14, 2003 Andrzej Szpilman, son of Wladyslaw Szpilman – The Pianist, was featured for an evening of talk and music at the Polish Embassy in Washington, DC. The event was co-sponsored by The Thursday Dinner Society as inspired by Polish King Stanislaw August Poniatowski.

Szpilman (left) addressed the audience at length concerning the life and times of his now famous father. He told the very interesting story of how and why his father wrote the book The Pianist: The Extraordinary True Story of One Man’s Survival in Warsaw, 1939-1945. Recently the book was made into the celebrated and internationally acclaimed movie The Pianist by director Roman Polanski.

Also recounted were many personal and professional anecdotes and vignettes on all aspects of Wladyslaw Szpilman’s life which held the audience spellbound for over one hour. The Szpilman presentation was followed by a lively and very informative question and answer period as well as an interlude of entertaining piano music and a sumptuous Polish buffet. Text and photographs by Richard P. 'Charming, effervescent, and strikingly American'.

Amazingly cool.' (The Holywood Reporter) From Universal Records SONGS COMPOSED BY WLADYSLAW SZPILMAN 12 popular songs wonderfully performed by Wendy Lands SONGBOOK “My memories of you” Sixteen selected songs by Wladyslaw Szpilman by Boosey & Hawkes Publishers Some of Wladyslaw Szpilman's most popular songs from the 30s to the 70s have been recorded on the new disc 'Wendy Lands Sing the Music of the Pianist Wladyslaw Szpilman'.

A selection of these timeless ballads are now published in their original version with piano accompaniment, for singers everywhere with newly commissioned English language lyrics by David Batteau, Michael Ruff, Carol Connor and others. Now from SONY Classical (Nr.: CD 93516) Wladyslaw Szpilman Works for Piano & Orchestra Concertino for piano and orchestra, Waltz in the Olden Style*, Paraphrase on an Original Theme*, Introduction to a Film* Little Overture, Ballet Scene*, Suite 'The Live of the Machines'*, Three Little Folk Song Suites* Ewa Kupiec - Piano, Rundfunk-Sinfonieorchester Berlin, Director - John Axelrod Recorded in Berlin on 26-28th June 2004, Published in first edition by Boosey & Hawkes in 2004 * World Premiere on CD. Num: 9973 Name: SZPILMAN Epoch of the osculating orbital elements (Modified Julian Date = Julian Date - 2400000.5): 53400 Semi-major axis (AU) a: 2.5307511 'e' Eccentricity: 0.17139580 'i (deg)'Inclination (degrees, J2000 ecliptic): 1.49867 'W (deg)' Longitude of the ascending node (degrees, J2000 ecliptic): 104.48204 Node: 297.24751 'M (deg)' Mean anomoly (degrees): 2 H: 14.20 G: 0.15 Ref: Minor Planet Center MPC40288 Discovery date: 1993 07 12 Discovery site: La Silla Discoverer: Elst, E.

Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis Claire Harrison, D.M., Jean-Jacques Kiladjian, M.D., Ph.D., Haifa Kathrin Al-Ali, M.D., Heinz Gisslinger, M.D., Roger Waltzman, M.D., M.B.A., Viktoriya Stalbovskaya, Ph.D., Mari McQuitty, R.N., M.P.H., Deborah S. Hunter, Ph.D., Richard Levy, M.D., Laurent Knoops, M.D., Ph.D., Francisco Cervantes, M.D., Ph.D., Alessandro M. Vannucchi, M.D., Tiziano Barbui, M.D., and Giovanni Barosi, M.D. N Engl J Med 2012; 366:787-798 DOI: 10.1056/NEJMoa1110556.

Results A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P. Figure 1 Changes in Spleen Volume and Spleen Length, According to Treatment Group. Panel A shows the percentage of patients in the efficacy-analysis population (all patients who underwent randomization and had both a baseline measurement and at least one subsequent assessment) who had a reduction in spleen volume of at least 35% from the baseline volume, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) at 48 weeks. Panel B shows the best percentage change from baseline in spleen volume, as assessed by MRI or CT, at any time within the first 48 weeks of treatment, among patients with a baseline assessment and at least one subsequent assessment. Data are shown for individual patients. Panel C shows the median length of time that a reduction of at least 35% in spleen volume, as assessed by MRI or CT, was maintained, among patients who were continuously receiving ruxolitinib. Patients were considered to have had a loss of response (event) if the spleen volume was no longer reduced by at least 35% from the baseline volume and was increased by 25% or more from the nadir.

Data from patients who did not have an assessment subsequent to the baseline assessment, or who were still having a response at the time of cutoff of the data, were censored. Panel D shows the mean percentage change from baseline in palpable spleen length over time. I bars represent standard errors. BAT denotes best available therapy.

Figure 2 Changes in Quality-of-Life and Symptom-Assessment Scores, According to Treatment Group. Mean changes from baseline at week 48 are shown for scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire core model (QLQ-C30) global health status–quality of life and selected functioning scores (Panel A); selected EORTC QLQ-C30 symptom scores (Panel B); and Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) scores, including total scores, disease-specific subscale (FACT-LymS) scores, Trial Outcome Index (FACT-TOI) scores (a summary of physical, functional, and disease-specific outcomes), and general (FACT-G) scores (Panel C).

In Panels A and C, improvement is represented by positive numbers, whereas in Panel B, improvement is represented by negative numbers (reduction in symptoms). For EORTC QLQ-C30 functioning and symptom subscales that are not shown, there only were minimal between-group differences (i.e., a difference of. Myelofibrosis, which can present as a primary disease or can evolve from polycythemia vera or essential thrombocythemia, is characterized by marrow fibrosis, progressive anemia, and extramedullary hematopoiesis, manifested primarily as splenomegaly. Severe constitutional symptoms (e.g., night sweats and weight loss), pruritus, fatigue, and sequelae of splenomegaly are common. The median survival from the time of diagnosis is 4 years for patients with intermediate-2–risk disease and 2 years for patients with high-risk disease.

Apart from allogeneic stem-cell transplantation, treatment is palliative and does not address the characteristic abnormality identified in myelofibrosis, a dysregulation of Janus kinase (JAK)–mediated cytokine and growth-factor signal transduction. In 2005, the JAK2 V617F mutation was identified as the most common molecular abnormality in myeloproliferative neoplasms.

Other mutations that activate the JAK pathway have been identified, including mutations in JAK2 exon 12, myeloproliferative leukemia virus oncogene ( MPL), and LNK. Thus, dysregulation of the JAK signaling pathway is frequently noted in patients who have myelofibrosis, with or without the V617F mutation. Ruxolitinib (also known as INC424 or INCB18424) is an orally bioavailable, potent, and selective inhibitor of JAK1 and JAK2 that is approved for the treatment of intermediate- and high-risk myelofibrosis. Ruxolitinib selectively inhibits the proliferation of JAK2 V617F-driven Ba/F3 cells, and these effects are correlated with decreased levels of phosphorylated JAK2 and of signal transducer and activator of transcription 5 (STAT5). In a phase 1–2 study of patients with myelofibrosis, ruxolitinib was associated with weight gain, prompt and marked reductions in spleen size, and reductions in debilitating symptoms.

We describe here results from the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment II (COMFORT-II), a randomized, phase 3 trial comparing ruxolitinib with the best available therapy in patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis. Eligibility Criteria Patients 18 years of age or older who had primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis and a palpable spleen 5 cm or more below the costal margin were eligible for the study, irrespective of their JAK2 V617F mutation status. Study Design Patients were stratified according to prognostic score at enrollment and were randomly assigned, in a 2:1 ratio, to receive ruxolitinib or the best available therapy, which included any commercially available agents (as monotherapy or in combination) or no therapy at all and which could be changed during the treatment phase. The starting dose of ruxolitinib tablets was 15 mg twice daily if the baseline platelet count was 200×10 9 per liter or less and 20 mg orally twice daily if the baseline platelet count was greater than 200×10 9 per liter.

A protocol-specified dosing regimen required reductions of the dose for reasons of safety (if neutropenia or thrombocytopenia developed) and permitted escalation of the dose to increase efficacy, although the dose could not exceed 25 mg twice daily. Patients received ruxolitinib or the best available therapy until the criteria for disease progression were met. At any time, patients who met protocol-specified criteria (underwent splenectomy or had an increase in spleen volume of >25% from the nadir during the study period, which could include the baseline volume) discontinued the randomized treatment phase of the study and could enter an extension phase. In the extension phase, patients who had been randomly assigned to the best available therapy could receive ruxolitinib if they met protocol-specified safety criteria, and patients who had been randomly assigned to ruxolitinib could continue to receive ruxolitinib if they were still deriving a clinical benefit. Patients who had leukemic transformation or underwent splenic irradiation were withdrawn from the study.

End Points The primary end point was a reduction of 35% or more in spleen volume from baseline at week 48. This end point was selected on the basis of the international response criterion of a reduction of 50% or more in spleen length as assessed by palpation and prior data showing a correlation of that measurement with a 33% reduction in spleen volume as measured by magnetic resonance imaging (MRI). Spleen volume was assessed by MRI or by computed tomography (CT) (in the case of patients who were not suitable candidates for MRI) every 12 weeks; the images were read by a reader at a central location who was unaware of the group assignments. Spleen and liver volumes were assessed by outlining the circumference of the organ and determining the volume using a least-squares analysis. Spleen length was assessed by manual palpation at every study visit. Throughout this report, measurements of spleen volume were performed by MRI or CT, whereas measurements of spleen length were performed by palpation.

The key secondary end point was a reduction of 35% or more in spleen volume from baseline at week 24. Additional secondary end points included the length of time that a reduction in spleen volume of at least 35% was maintained, the time to a reduction in spleen volume of 35% or more from baseline, progression-free survival, leukemia-free survival, overall survival, and change in marrow histomorphologic features.

Information regarding other secondary and exploratory end points and the definition of disease progression are provided in the. Symptoms and Quality of Life Symptoms and quality of life were assessed with the use of the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire core model (QLQ-C30) and the Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) scale. The EORTC QLQ-C30 includes five scales related to functioning, nine scales related to symptoms, and a global health status and quality-of-life scale.

The FACT-Lym consists of a general core questionnaire (FACT-G), a disease-specific questionnaire (Lymphoma Subscale [LymS]), and a trial outcome index (FACT-TOI), which is a summary index of physical, functional, and symptom outcomes. Safety The safety population consisted of all patients in the ruxolitinib group who received at least one dose of study drug and all patients in the best-available-therapy group. Adverse events were monitored continuously during the study and were graded according to the National Cancer Institute's Common Toxicity Criteria, version 3. Throughout the study, patients provided blood samples at specified times, and the samples were analyzed by the same laboratory throughout the study to ensure consistency in values. Study Oversight The study was sponsored by Novartis Pharmaceuticals and designed by Incyte.

It was approved by the institutional review board at each participating institution, and was conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent. Data were analyzed and interpreted by the sponsor's clinical and statistical teams in collaboration with authors who were not affiliated with the sponsor. An independent data and safety monitoring board reviewed the trial data and made recommendations regarding the continuation of the study. The first author prepared the first draft of the manuscript, with assistance from a medical writer who was funded by Novartis Pharmaceuticals, and made the final decision to submit the manuscript for publication.

All the authors and representatives of the sponsor reviewed and amended the manuscript. All the authors vouch for the accuracy and completeness of the data and verify that the study as reported conforms to the and statistical analysis plan (both of which are available at NEJM.org). Statistical Analysis The efficacy analysis was performed according to the intention-to-treat principle, with data from all patients who underwent randomization. The database cutoff date was January 4, 2011, the date on which the last patient completed the week 48 study visit. Patients who did not undergo an assessment of spleen volume at week 48 were considered not to have had a response. The two groups were compared with the use of the exact Cochran–Mantel–Haenszel test, stratified according to prognostic category (intermediate-2 risk or high risk). The family-wise alpha level was controlled at 0.05 overall for two prespecified comparisons (the primary and key secondary end points).

The key secondary end point was to be tested only if the primary end point showed significance at a two-sided alpha level of 0.05. No formal adjustment for multiple comparisons has been made. Survival curves for leukemia-free survival, overall survival, and progression-free survival were estimated with the use of the Kaplan–Meier method. Hazard ratios and the corresponding 95% confidence intervals were estimated with the use of the Cox proportional-hazards model, stratified according to baseline prognostic category; the between-group treatment difference was tested with the use of a stratified two-sided log-rank test. Characteristics of the Patients During the period from July 1, 2009, through January 22, 2010, a total of 219 patients underwent randomization, of whom 146 were assigned to receive ruxolitinib and 73 were assigned to receive the best available therapy. The baseline characteristics were balanced between the groups ( Table 1 Baseline Characteristics of the Study Patients. Approximately half the patients had primary myelofibrosis, approximately one third had post–polycythemia vera myelofibrosis, and the remainder had post–essential thrombocythemia myelofibrosis.

Approximately 40% of the patients in each study group were classified as having disease of intermediate-2 risk, and 60% were classified as having high-risk disease. Treatment with ruxolitinib was initiated at a dose of 15 mg twice daily in 38% of the patients and at a dose of 20 mg twice daily in 62%. The median dose intensity of ruxolitinib was 30 mg per day (range, 10 to 49). Among patients receiving the best available therapy, the most common therapies were antineoplastic agents (in 51%) — most frequently hydroxyurea (47%) — and glucocorticoids (16%); a total of 33% of patients received no therapy (Table 2 in the ). As of the data cutoff date (January 4, 2011), a smaller percentage of patients in the ruxolitinib group than in the best-available-therapy group had discontinued the randomized treatment phase of the study (38% vs. Of the 55 patients who had been randomly assigned to receive ruxolitinib and who discontinued the randomized treatment phase owing to protocol-specified criteria, 29 (53%) entered the extension phase and continued to receive ruxolitinib because they were still deriving clinical benefits.

Of the 42 patients who had originally been assigned to receive the best available therapy and who discontinued the randomized treatment phase for any reason, 18 (43%) met protocol-specified criteria for crossover to ruxolitinib in the extension phase. Information on patient disposition is provided in Figure 1 and Table 3 in the.

The data included in this article are those from the randomized treatment phase only. Assessments of Spleen Volume and Length The efficacy analyses included all 219 patients who underwent randomization (146 in the ruxolitinib group and 73 in the group receiving the best available therapy). Three patients (two in the ruxolitinib group and one in the group receiving the best available therapy) underwent baseline MRI assessments of spleen volume after randomization and were not included in the efficacy analyses of spleen volume. At week 48, most of the patients in the ruxolitinib group had a reduction in spleen volume ( Figure 1 Changes in Spleen Volume and Spleen Length, According to Treatment Group.

Panel A shows the percentage of patients in the efficacy-analysis population (all patients who underwent randomization and had both a baseline measurement and at least one subsequent assessment) who had a reduction in spleen volume of at least 35% from the baseline volume, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) at 48 weeks. Panel B shows the best percentage change from baseline in spleen volume, as assessed by MRI or CT, at any time within the first 48 weeks of treatment, among patients with a baseline assessment and at least one subsequent assessment. Data are shown for individual patients. Panel C shows the median length of time that a reduction of at least 35% in spleen volume, as assessed by MRI or CT, was maintained, among patients who were continuously receiving ruxolitinib. Patients were considered to have had a loss of response (event) if the spleen volume was no longer reduced by at least 35% from the baseline volume and was increased by 25% or more from the nadir. Data from patients who did not have an assessment subsequent to the baseline assessment, or who were still having a response at the time of cutoff of the data, were censored.

Panel D shows the mean percentage change from baseline in palpable spleen length over time. I bars represent standard errors. BAT denotes best available therapy. Only patients in the ruxolitinib group met the criterion for the primary end point, at least a 35% reduction in spleen volume from baseline at 48 weeks (28%, vs. 0% in the group receiving the best available therapy; P. Survival Assessments By the data cutoff date at a median of 12 months of follow-up, 124 patients who had been randomly assigned to the ruxolitinib group and 50 patients who had been randomly assigned to the best-available-therapy group were alive and still being followed for the prespecified secondary survival end points beyond 48 weeks. In a time-to-event analysis, conducted at week 48, there were 44 patients in the ruxolitinib group (30%) who had progression events, as compared with 19 (26%) in the group receiving the best available therapy (hazard ratio for progression with ruxolitinib, 0.81; 95% CI, 0.47 to 1.39).

In the analyses of leukemia-free survival and overall survival, there were 10 events in total (all of which were deaths): 6 events (4%) with ruxolitinib, as compared with 4 events (5%) with the best available therapy (hazard ratio for leukemia-free survival with ruxolitinib, 0.65; 95% CI, 0.18 to 2.31; hazard ratio for overall survival, 0.70; 95% CI, 0.20 to 2.49). In an analysis performed for a planned safety update with approximately 2 months of additional follow-up (median, 61.1 weeks), a total of 11 deaths (8%) were reported in the ruxolitinib group and 4 (5%) in the group receiving the best available therapy (hazard ratio, 1.01; 95% CI, 0.32 to 3.24).

The median survival time has not been reached. The study was not powered to detect differences in time-to-event end points, and a limited number of patients remain in the group receiving the best available therapy for further time-to-event end-point analyses.

Marrow Histomorphologic and Biomarker Assessments No major changes in marrow histomorphologic features were observed in a prespecified secondary analysis of data from patients receiving any therapy. In a prespecified exploratory analysis, ruxolitinib treatment was associated with changes in plasma biomarkers (Table 5 in the ); levels of several proinflammatory cytokines, including interleukin-6, tumor necrosis factor alpha, and C-reactive protein were reduced, whereas erythropoietin and leptin levels were increased. Symptoms and Other Patient-Reported Outcomes In prespecified exploratory analyses of patient-reported outcomes (as assessed by means of the EORTC QLQ-C30 and FACT-Lym subscales), patients in the ruxolitinib group, as compared with patients receiving the best available therapy, had improved quality-of-life and role functioning ( Figure 2 Changes in Quality-of-Life and Symptom-Assessment Scores, According to Treatment Group.

Mean changes from baseline at week 48 are shown for scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire core model (QLQ-C30) global health status–quality of life and selected functioning scores (Panel A); selected EORTC QLQ-C30 symptom scores (Panel B); and Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) scores, including total scores, disease-specific subscale (FACT-LymS) scores, Trial Outcome Index (FACT-TOI) scores (a summary of physical, functional, and disease-specific outcomes), and general (FACT-G) scores (Panel C). In Panels A and C, improvement is represented by positive numbers, whereas in Panel B, improvement is represented by negative numbers (reduction in symptoms). For EORTC QLQ-C30 functioning and symptom subscales that are not shown, there only were minimal between-group differences (i.e., a difference of.

Safety Both ruxolitinib and the best available therapy were associated with few grade 3 or 4 nonhematologic adverse events, regardless of whether they were thought to be related to the study drug ( Table 2 Nonhematologic and Serious Adverse Events, Regardless of Whether They Were Related to the Study Drug. ), and the percentage of patients who discontinued treatment owing to adverse events was small in both groups (8% in the ruxolitinib group and 5% in the best-available-therapy group). The most frequently reported nonhematologic adverse event of any grade in the ruxolitinib group was diarrhea (with diarrhea of any grade occurring in 23% of the patients and grade 3 or 4 diarrhea occurring in 1%); diarrhea was also the only adverse event with a difference in incidence of 10% or more between the ruxolitinib group and the best-available-therapy group. Peripheral edema was the most frequently reported adverse event in the group receiving the best available therapy. The most frequently reported grade 3 or 4 nonhematologic adverse events were abdominal pain in the ruxolitinib group (occurring in 3% of the patients) and dyspnea and pneumonia in the group receiving the best available therapy (each occurring in 4% of the patients). The patients in the ruxolitinib group had a mean gain in body weight of 4.43 kg by week 48, whereas the mean body-weight gain in the best-available-therapy group was minimal (0.03 kg).

Thrombocytopenia and anemia occurred more frequently in the patients receiving ruxolitinib than in those receiving the best available therapy ( Table 3 Hemoglobin and Platelet–Count Abnormalities, According to Study Group and Grade. ), a finding that is consistent with the known mechanism of action of ruxolitinib, but these events rarely led to treatment discontinuation (one patient in each group discontinued the study owing to thrombocytopenia) and were generally manageable with dose modifications, transfusions of packed red cells, or both. Mean hemoglobin levels in the ruxolitinib group declined from the baseline level of 109.3 g per liter to a nadir of 94.1 g per liter at approximately 12 weeks of therapy and then increased to a steady state (101.8 g per liter) by week 24 (Fig.

Modifications of the ruxolitinib dose were mandated if thrombocytopenia or neutropenia developed. Adverse events of any grade requiring dose reductions or interruptions occurred more frequently with ruxolitinib than with the best available therapy (in 63% of patients vs. Thrombocytopenia was the most common cause of dose modifications in both groups (in 41% of the patients in the ruxolitinib group and 1% in the best-available-therapy group). Only 5% of the patients in the ruxolitinib group required dose interruptions or reductions owing to anemia and 1% owing to neutropenia; the corresponding percentages in the best-available-therapy group were 1% and 0%. During the treatment period, more patients in the ruxolitinib group than in the best-available-therapy group received at least one transfusion of packed red cells (51% vs.

The mean number of transfusions per month was similar in the two treatment groups (0.86 and 0.91, respectively). In the ruxolitinib group, the percentage of patients who required transfusions of packed red cells was higher among those who started ruxolitinib at a dose of 20 mg twice daily than among those who started at 15 mg twice daily (58% vs. Serious adverse events were balanced between the two groups ( ). The most frequently reported serious adverse event in both groups was anemia (in 5% of the patients in the ruxolitinib group and 4% in the best-available-therapy group). Pneumonia was the only serious adverse event reported in 5% or more of patients in either group (1% in the ruxolitinib group and 5% in the best-available-therapy group).

Among the 32 patients who discontinued ruxolitinib, 19 had adverse events 2 weeks or less after discontinuation. Of these 19 patients, 6 patients had at least one symptom referable to myelofibrosis, including general deterioration in physical health (1 patient), pyrexia (2), anorexia (2), fatigue (1), weight loss (2), night sweats (1), and pruritus (1). Three of these events — general deterioration in physical health, pyrexia, and fatigue — were reported as grade 3 events. Among the remaining patients who discontinued ruxolitinib, there was no pattern with respect to the type or severity of the event. At 12 months of follow-up, 10 deaths had been reported (6 in the ruxolitinib group [4%] and 4 in the best-available-therapy group, [5%]), of which 7 deaths (4 [3%] and 3 [4%] in the two groups, respectively) occurred within 28 days after discontinuation of the study treatment.

With an additional 2 months of follow-up (median total follow-up, 61.1 weeks), an additional 5 deaths occurred in the ruxolitinib group. Discussion This randomized, phase 3 study shows the superiority of a JAK1 and JAK2 inhibitor over the best available therapy with respect to clinically relevant end points in patients with myelofibrosis.

Ruxolitinib resulted in a rapid reduction in splenomegaly (at weeks 24 and 48). The meaningful overall reductions in debilitating symptoms of myelofibrosis and improvements in role functioning, which were observed by week 8 and continued through week 48, attest to the beneficial effects of ruxolitinib on quality of life in patients with myelofibrosis. In addition to these reductions in splenomegaly and myelofibrosis-associated symptoms, ruxolitinib resulted in changes in cytokine levels that were similar to those that have been reported previously and that have been implicated in the clinical phenotype of myelofibrosis. In contrast, the best available therapy was associated with a median increase in spleen volume and a worsening of symptoms. Ruxolitinib was associated with increased frequencies of anemia and thrombocytopenia, findings that are consistent with the results of previous studies. Anemia and thrombocytopenia could generally be managed with dose reductions or brief interruptions of ruxolitinib therapy, and treatment had to be discontinued in only one patient in the ruxolitinib group owing to thrombocytopenia and in none owing to anemia.

More patients in the ruxolitinib group than in the best-available-therapy group required transfusions of packed red cells to treat anemia, though the mean number of units transfused per patient was similar in the two treatment groups. Some differences in response rates were detected between patients with the wild-type allele and those with the JAK2 V617F mutation. However, the overall similarity in responses across subgroups suggests that these factors may not be useful prerequisites for the consideration of ruxolitinib therapy. Longer follow-up will be needed to assess changes in marrow fibrosis and the JAK2 V617F allele burden. Although no benefit of ruxolitinib was observed with respect to overall survival, at the updated analysis, approximately 25% of the patients who had been assigned to receive the best available therapy had crossed over to ruxolitinib, and an additional 12% had withdrawn consent, with no additional follow-up for survival. This limits the interpretation of the survival analysis because of confounding survival data for one third of the patients in the best-available-therapy group. In summary, this study shows that continuous oral ruxolitinib therapy can reduce splenomegaly and improve quality of life in patients with myelofibrosis.

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